Prerpints.org logo
Preprint
Article

Machine Learning Discoveries of ABC Transporter-X Synergy in ETC-1922159 Treated Colorectal Cancer Cells

Altmetrics

Downloads

43

Views

65

Comments

0

This version is not peer-reviewed

Advances in Colorectal Cancer Therapy

Submitted:

05 September 2024

Posted:

11 September 2024

You are already at the latest version

Alerts
Abstract
Often, in biology, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combinations of factors/genes/proteins that might be affecting the pathway under certain conditions. In colorectal cancer (CRC) cells treated with ETC-1922159, many genes were found up and down regu- lated, individually. A recently developed search engine ranked combinations of ATP- binding cassette (ABC) transporters-X (X, a particular gene/protein) at 2nd order level after drug administration. These rankings reveal which ABC-X combinations might be working synergistically in CRC. If found true, oncologists can further test the com- bination of interest in wet lab and determine the mechanism of functioning between the ABC and X. In this research work, we cover combinations of ABC with ubiquitin- conjugating enzymes (UBE2), Interleukin (IL), BCL and Caspase (CASP).
Keywords: 
Subject: Computer Science and Mathematics  -   Mathematical and Computational Biology

1. Introduction

In the unpublished preprint Sinha [1], a frame work of a search engine was developed which can rank combinations of factors (genes/proteins) in a signaling pathway. Such combinations are of import due to the vast search space in which they exist and the difficulty to find them. The search engine facilitates in prioritizing the combinations as ranked biological hypotheses which the biologists might want to test in wet lab, to know if a synergistic combination is prevalent in a signaling pathway, in a direct or indirect manner. Interested readers are advised to go through unpublished preprints Sinha [1] and Sinha [2] for details regarding the search engine and the discoveries mentioned in there.

2. Materials and Methods

2.1. Combinatorial Search Problem and a Possible Solution

The issue of combinatorial search problem and a possible solution has been addressed in Sinha [3] and Sinha [2]. The details of the methodology of this manuscript have been explained in great detail in Sinha [3] & its application in Sinha [2]. Readers are requested to go through the same for gaining deeper insight into the working of the pipeline and its use of published data set generated after administration of ETC-1922159. In order to understand the significance of the solution proposed to the problem of combinatorial search that the biologists face in revealing unknown biological search problem, these works are of importance. Briefly, from Sinha [2], the pipleline works by computing sensitivity indicies for each of these unique combinations and then vectorising these indices to connote and form discriminative feature vector for each combination. Since each combination is unique, the training and the test data are same. In the training data, the combinations are arranged and ranks from 1 to n are assigned. The ranking algorithm then learns the patterns from these combinations/sensitivity index vectors. Next the learned model is used to rank the test data by generating the ranking score for each of the unique combination. Sorting these shuffled scores of test data leads to prioritization of the combinations. Joachims [4] show an example of applying learned model to training data (same as the test data) in https://www.cs.cornell.edu/people/tj/svm_light/svm_rank.html. Note that these combinations are now ranked and give the biologists a chance to narrow down their focus on crucial biological hypotheses in the form of combinations which the biologists might want to test. Analogous to the webpage search engine, where the click of a button for a few key-words leads to a ranked list of web links, the pipeline uses sensitivity indices as an indicator of the strength of the influence of factors or their combinations, as a criteria to rank the combinations.

3. Results & Discussion

3.1. ABC Transporter Related Synergies

3.1.1. ABC Transporters - UBE2 Cross Family Analysis

Not much is known about the interaction or any possible direct/indirect synergy of ABC transporters and the Ubiquitin-conjugating enzyme E2 family. In CRC cells treated with ETC-1922159, family members of both were found to be up regulated. The search engine also assigned numerically high valued ranks to a few of 2nd order synergies between the the two. We document here these synergies and show the possible unexplored combinations between the two familes. Table 1 and Table 2 show the rankings of ABC w.r.t UBE2 and vice versa, respectively.
In Table 1 we found ABC-C3 up regulated w.r.t UBE2-A. This is reflected in the rankings of 2137 (laplace) and 2491 (linear) for ABC-C3 - UBE2-A. ABC-C5 was up regulated w.r.t UBE2-B. This is reflected in the rankings of 2317 (laplace) and 2266 (rbf) for ABC-C5 - UBE2-B. ABC-A5/D1/G2 were up regulated w.r.t UBE2-F. These are reflected in the rankings of 2408 (linear) and 1784 (rbf) for ABC-A5 - UBE2-F, 2069 (linear) and 1959 (rbf) for ABC-D1 - UBE2-F and 1995 (linear) and 2120 (rbf) for ABC-G2 - UBE2-F. ABC-A5/C13 were up regulated w.r.t UBE2-H. These are reflected in 2068 (linear) and 2438 (rbf) for ABC-A5 - UBE2-H and 2492 (linear) and 2051 (rbf) for ABC-C13 - UBE2-H. ABC-C13 was up regulated w.r.t UBE2-J1. This is reflected in the rankings of 2095 (laplace), 2412 (linear) and 2360 (rbf). ABC-C5 was up regulated w.r.t UBE2-Z. This is reflected in rankings of 2348 (laplace) and 1859 (rbf) for ABC-C5 - UBE2-Z. In Table 2 we found UBE2-A up regulated w.r.t ABC-C5/G2. This is reflected in the rankings of 2122 (linear) and 2297 (rbf) for ABC-C5 - UBE2-A; and 2048 (laplace) and 1829 (linear) for ABC-G2 - UBE2-A. UBE2-B up regulated w.r.t ABC-A5/C3/C13/D1/G2. This is reflected in the rankings of 1846 (laplace) and 2038 (linear) for ABC-A5 - UBE2-B; 1999 (laplace) and 2050 (rbf) for ABC-C3 - UBE2-B; 1863 (linear) and 2496 (rbf) for ABC-C13 - UBE2-B; 2322 (laplace), 1917 (linear) and 2426 (rbf) for ABC-D1 - UBE2-B and 1833 (laplace), 2445 (linear) and 2506 (rbf) for ABC-G2 - UBE2-B. UBE2-F was found up regulated w.r.t ABC-B11/C3/D1/G1. These were reflected in 2003 (laplace) and 2422 (rbf) for ABC-B11 - UBE2-F; 2132 (laplace) and 2163 (linear) for ABC-C3 - UBE2-F; 2421 (laplace) and 2176 (rbf) for ABC-D1 - UBE2-F; and 2202 (laplace) and 1953 (rbf) for ABC-G1 - UBE2-F. UBE2-H was found to be up regulated w.r.t ABC-B11/C3/C5/C13/G1. These are reflected in rankings of 1950 (laplace), 1770 (linear) and 2461 (rbf) for ABC-B11 - UBE2-H; 2439 (laplace), 1972 (linear) and 2305 (rbf) for ABC-C3 - UBE2-H; 2473 (linear) and 2355 (rbf) for ABC-C5 - UBE2-H; 2004 (laplace), 2317 (linear) and 1847 (rbf) for ABC-C13 - UBE2-H; and 1921 (linear) and 2288 (rbf) for ABC-G1 - UBE2-H; UBE2-J1 was found to be up regulated w.r.t ABC-B11/C3/C13/D1/G1/G2; 1806 (laplace) and 1935 (rbf) for ABC-B11 - UBE2-J1; 2073 (laplace) and 2291 (linear) for ABC-C3 - UBE2-J1; 2329 (laplace), 2153 (linear) and 1951 (rbf) ABC-C13 - UBE2-J1; 2263 (laplace), 1886 (linear) and 2249 (rbf) for ABC-D1 - UBE2-J1; and 2418 (linear) and 2277 (rbf) for ABC-G1 - UBE2-J1; Finally, UBE2-Z was found up regulated w.r.t ABC-C3/D1/G1/G2. These are reflected in rankings of 1978 (laplace), 1823 (linear) and 1859 (rbf) for ABC-C3 - UBE2-Z; 2292 (laplace) and 2381 (linear) for ABC-D1 - UBE2-Z; 2515 (linear) and 1858 (rbf) for ABC-G1 - UBE2-Z; 2270 (laplace), 2080 (linear) and 2448 (rbf) for ABC-G2 - UBE2-Z. Table 3 shows the derived influences which can be represented graphically, with the following influences - • ABC w.r.t UBE2 with ABC-C3 < − UBE2-A; ABC-C5 < − UBE2-B; ABC-A5/D1/G2 < − UBE2-F; ABC-A5/C13 < − UBE2-H; ABC-C13 < − UBE2-J1; ABC-C5 < − UBE2-Z; and • UBE2 w.r.t ABC with UBEA-2 < − ABC-C5/G2; UBE2-B < − ABC-A5/C3/C13/D1/G2; UBE2-F < − ABC-B11/C3/D1/G1; UBE2-H < − ABC-B11/C3/C5/C13/G1; UBE2-J1 < − ABC-B11/C3/C13/D1/G1/G2; UBE2-Z < − ABC-C3/D1/G1/G2.

3.1.2. ABC Transporters Intra Cross Family Analysis

A range of ABC transporters were found to be up regulated in CRC cells after ETC-1922159 treatment. We checked the rankings of the ABC transporters within the ABC family and found multiple synergistic upregulation at 2nd order level that were ranked appropriately. Table 4 shows intra family rankings of ABC members among themselves. We found ABC-C13 upregulated w.r.t ABC-A5. These were reflected in rankings of 1943 (linear) and 2151 (rbf); ABC-C5/C13/G1 were up regulated w.r.t ABC-B11. These are reflected in rankings of 2226 (laplace) and 2241 (rbf) for ABC-C5 - ABC-B11; 1971 (laplace) and 2150 (rbf) for ABC-C13 - ABC-B11 and 1957 (laplace) and 1920 (linear) for ABC-G1 - ABC-B11; ABC-C3/C13 were found to be up regulated w.r.t ABC-C5. These are reflected in 2084 (laplace), 2274 (linear) and 1758 (rbf) for ABC-C3 - ABC-C5 and 2476 (linear) and 2446 (rbf) for ABC-C13 - ABC-C5. ABC-C5/C13 were found to be up regulated w.r.t ABC-D1. 2423 (laplace) and 2388 (rbf) for ABC-C5 - ABC-D1 and 2383 (laplace) and 2029 (linear) for ABC-C13 - ABC-D1. ABC-A5 was found to be up regulated w.r.t ABC-G1. This is reflected in rankings of 2488 (laplace) and 1776 (linear) for ABC-A5 - ABC-G1. ABC-A5 was found to be up regulated w.r.t ABC-G2 also. This is reflected in rankings of 2284 (laplace), 1904 (linear) and 1829 (rbf) for ABC-A5 - ABC-G2.
Table 5 shows the derived influences which can be represented graphically, with the following influences - • ABC intra family with ABC-C13 < − ABC-A5; ABC-C5/C13/G1 < − ABC-B11; ABC-C3/C13 < − ABC-C5; ABC-C5/C13 < − ABC-D1; ABC-A5 < − ABC-G1; ABC-C5 < − ABC-G2.

3.1.3. Interleukin - ABC Transporters Cross Family Analysis

Zhou et al. [5] have observed that the ABCA1 contributes to the secretion of interleukin 1 β from macrophages. Haskó et al. [6] show that inhibitors of ABC transporters suppress interleukin-12 p40 production and major histocompatibility complex II up-regulation in macrophages. Park et al. [7] conclude that anti-cancer drug-induced IL-8 secretion increased the expression of ABC transporters and SP cells, promoting the growth of HCC in vitro. Marty et al. [8] show that ABC1 is required for the release of interleukin-1 β by P2X7-stimulated and lipopolysaccharide-primed mouse Schwann cells. Lottaz et al. [9] observe that inhibition of ABC transporter downregulates interleukin-1 β -mediated autocrine activation of human dermal fibroblasts. These findings and many more indicate the synergy between IL family and ABC transporters. In colorectal cancer cells treated with ETC-1922159, some of the members of both families were up regulated. Given the studied synergies, our search engine found multiple combinations which were ranked with high numerical values, thus indicating possible dual combinatorial role. Table 6 and Table 7, each show rankings of ABC transporters w.r.t IL family on the left half and vice versa on the right half. On the left half we found IL-17REL up regulated w.r.t ABCA5. This is reflected in the rankings of 2405 (linear) and 2202 (rbf) for IL17REL - ABCA5. IL-2RG/6ST/15/15RA up regulated w.r.t ABCB11. This is reflected in the rankings of 2182 (laplace), 2102 (linear) and 550 (rbf) for IL2RG - ABCB11; 1793 (laplace), 2140 (linear) and 1938 (rbf) for IL6ST - ABCB11; 2438 (laplace) and 2512 (linear) for IL15 - ABCB11; and 2271 (laplace) and 1784 (rbf) for IL15RA - ABCB11. IL-8/15RA up regulated w.r.t ABCC3. This is reflected in the rankings of 1767 (laplace) and 2419 (rbf) for IL8 - ABCC3 and 2403 (linear) and 1795 (rbf) for IL15RA - ABCC3. IL-15RA/17REL up regulated w.r.t ABCC5. These are reflected in rankings of 2255 (linear) and 1861 (rbf) for IL15RA - ABCC5 and 2462 (linear) and 2509 (rbf) for IL17REL - ABCC5. IL-15RA/17REL were up regulated w.r.t ABCC13. These are reflected in 2248 (laplace), 1955 (linear) and 2456 (rbf) for IL15RA - ABCC13 and 2339 (laplace) and 2137 (linear) for IL17REL - ABCC13. IL-1A/1RAP/8/15RA were up regulated w.r.t ABCD1. These are reflected in rankings of 1932 (laplace) and 2203 (rbf) for IL1A - ABCD1; 2508 (laplace), 2006 (linear) and 1907 (rbf) for IL1RAP - ABCD1; 2010 (laplace), 2315 (linear) and 1814 (rbf) for IL8 - ABCD1; and 2097 (laplace) and 1765 (linear) for IL15RA - ABCD1. IL-1RAP was up regulated w.r.t ABCG1. This was reflected in rankings of 2205 (linear) and 2339 (rbf) for IL1RAP - ABCG1. IL-1RAP/15RA were up regulated w.r.t ABCG2. These were reflected in rankings of 2184 (laplace) and 2167 (linear) for IL1RAP - ABCG2 and 1910 (laplace), 2428 (linear) and 1921 (rbf) for IL15RA - ABCG2.
On the right half we found ABCA5 up regulated w.r.t IL-1B/1RAP/10RB. These are reflected in the rankings of 2069 (laplace) and 2301 (rbf) for IL1B - ABCA5; 1763 (laplace) and 2345 (rbf) for IL1RAP - ABCA5; and 2230 (laplace), 2184 (linear) and 2240 (rbf) for IL10RB - ABCA5; ABCB11 was up regulated w.r.t IL-10RB. This is reflected in the rankings of 2101 (laplace) and 2419 (linear) for IL10RB - ABCB11. ABCC3 was up regulated w.r.t IL-1A/17REL. This is reflected in the rankings of 1798 (linear) and 2459 (rbf) for IL1A - ABCC3 and 2089 (laplace) and 2388 (linear) for IL17REL - ABCC3. ABCC5 was up regulated w.r.t IL-1A/1RAP/15/17C. This are reflected in the rankings of 2217 (laplace) and 2022 (linear) for IL1A - ABCC5; 1982 (laplace), 1892 (linear) and 2296 (rbf) for IL1RAP - ABCC5; 1947 (laplace) and 1991 (linear) for IL15 - ABCC5 and 1836 (laplace) and 1802 (rbf) for IL17C - ABCC5. ABCC13 was up regulated w.r.t IL-1RAP/15RA. This are reflected in the rankings of 2136 (laplace) and 2392 (linear) for IL1RAP - ABCC13 and 2397 (laplace) and 2485 (linear) for IL15RA - ABCC13; ABCD1 was up regulated w.r.t IL-8/10RB. This are reflected in the rankings of 2501 (laplace) and 2154 (linear) for IL8 - ABCD1 and 1795 (laplace) and 2325 (rbf) for IL10RB - ABCD1. ABCG2 was up regulated w.r.t IL-10RB. This is reflected in the rankings of 2144 (laplace), 2335 (linear) and 2434 (rbf) for IL10RB - ABCG2.
Table 8 shows the derived influences which can be represented graphically, with the following influences - • ABC w.r.t IL with IL-1B/1RAP/10RB − > ABCA5; IL-10RB − > ABCB11; IL-1A/17REL − > ABCC3; IL-1A/1RAP/15/17C − > ABCC5; IL-1RAP/15RA − > ABCC13; IL-8/10RB − > ABCD1 and IL-10RB − > ABCG2; • IL w.r.t ABC with IL-17REL < − ABCA5; IL-2RG/6ST/15/15RA < − ABCB11; IL-8/15RA < − ABCC3; IL-15RA/17REL < − ABCC5; IL-15RA/17REL < − ABCC13; IL-1A/1RAP/8/15RA < − ABCD1; IL-1RAP < − ABCG1 and IL-1RAP/15RA < − ABCG2;

3.1.4. BCL - ABC Transporters Cross Family Analysis

Ruzickova et al. [10] show clinically relevant interactions of anti-apoptotic Bcl-2 protein inhibitors with ABC transporters. Alla et al. [11] observe that E2F1 confers anticancer drug resistance by targeting ABC transporter family members and Bcl-2 via the p73/DNp73-miR-205 circuitry. Yasui et al. [12] show a range of ABC family members along with BCL member to be overexpressed while studying the alteration in copy numbers of genes as a mechanism for acquired drug resistance. These point to the possible synergistic workings of BCL with ABC. In colorectal cancer cells treated with ETC-1922159, these were found to be up regulated. The search engine pointed to some of these 2nd order combinations and alloted rankings of high numerical value, thus indicating possible synergy. Table 9 and Table 10 show rankings of BCL family w.r.t ABC members on the left half and vice versa on the right half.
On the left half we found BCL2L1 up regulated w.r.t ABCC5. This is reflected in the rankings of 2239 (laplace) and 1845 (linear). BCL2L2 was up regulated w.r.t ABC-B11/C5/C13/D1. These are reflected in the rankings of 2097 (laplace) and 2311 (rbf) for ABCB11 - BCL2L2; 2195 (laplace), 2359 (linear) and 2322 (rbf) for ABCC5 - BCL2L2; 2438 (laplace) and 2494 (linear) for ABCC13 - BCL2L2 and 2477 (laplace) and 2156 (rbf) for ABCD1 - BCL2L2. BCL2L13 was up regulated w.r.t ABC-B11/C5/C13/D1/G1. These are reflected in the rankings of 2505 (laplace) and 1855 (rbf) for ABCB11 - BCL2L13; 1835 (linear) and 2178 (rbf) for ABCC5 - BCL2L13; 2484 (laplace), 2184 (linear) and 2410 (rbf) for ABCC13 - BCL2L13; 2472 (laplace) and 2201 (rbf) for ABCD1 - BCL2L13 and 2276 (linear) and 2095 (rbf) for ABCG1 - BCL2L13. BCL3 was up regulated w.r.t ABC-D1/G1. These are reflected in the rankings of 2194 (linear) and 2106 (rbf) for ABCD1 - BCL3 and 2014 (laplace) and 2253 (rbf) for ABCG1 - BCL3. BCL6 was up regulated w.r.t ABC-B11. These are reflected in the rankings of 2010 (linear) and 2350 (rbf) for ABC-B11 - BCL6. BCL10 was up regulated w.r.t ABC-B11. These are reflected in the rankings of 2234 (laplace) and 2382 (rbf) for ABC-B11 - BCL10.
On the right half we found ABCC3 up regulated w.r.t BCL2L1. This is reflected in the rankings of 2085 (laplace) and 2309 (linear) for ABCC3 - BCL2L1. ABC-C5/C13 were up regulated w.r.t BCL2L13. These was reflected in the rankings of 1975 (laplace) and 2421 (linear) for ABCC5 - BCL2L13; and 1894 (laplace), 2335 (linear) and 2475 (rbf) for ABCC13 - BCL2L13. ABC-C3 was up regulated w.r.t BCL3. This is reflected in the rankings of 1782 (linear) and 2186 (rbf) for ABCC3 - BCL3. ABC-C5/C13 were up regulated w.r.t BCL6. This is reflected in the rankings of 1841 (linear) and 2389 (rbf) for ABCC5 - BCL6 and 2172 (laplace) and 2456 (linear) for ABCC13 - BCL6. ABC-C5/C13/D1 were up regulated w.r.t BCL9L. This is reflected in the rankings of 1775 (laplace) and 2073 (rbf) for ABCC5 - BCL9L; 2475 (linear) and 2325 (rbf) for ABCC13 - BCL9L and 2440 (linear) and 2411 (rbf) for ABCD1 - BCL9L; ABC-A5/C5/C13/D1 were up regulated w.r.t BCL10. These were reflected in the rankings of 1753 (laplace) and 2312 (rbf) for ABCA5 - BCL10; 1775 (laplace) and 2073 (rbf) for ABCC5 - BCL10; 2475 (linear) and 2325 (rbf) for ABCC13 - BCL10 and 2440 (linear) and 2411 (rbf) for ABCD1 - BCL10.
Table 11 shows the derived influences which can be represented graphically, with the following influences - • BCL w.r.t ABC with ABC-C5 − > BCL2L1; ABC-B11/C5/C13/D1 − > BCL2L2; ABC-B11/C5/C13/D1/G1 − > BCL2L13; ABC-D1/G1 − > BCL3; ABC-B11 − > BCL6; ABC-B11 − > BCL10; and • ABC w.r.t BCL with ABC-C3 < − BCL2L1; ABC-C5/C13 < − BCL2L13; ABC-C3 < − BCL3; ABC-C5/C13 < − BCL6; ABC-C5/C13/D1 < − BCL9L; ABC-A5/C5/C13/D1 < − BCL10.

3.1.5. CASPASE - ABC transporters cross family analysis

Hu et al. [13] observe that the loss of ABCB4 attenuates the caspase-dependent apoptosis regulating resistance to 5-Fu in colorectal cancer. Ihlefeld et al. [14] analyze whether the observed upregulation of the multidrug transporters contributed to the resistance of Sgpl1/-MEFs against chemotherapy-induced apoptosis by measuring the influence of ABC transporter inhibitors on cell viability and caspase-3 cleavage. Though recent developements, they point to the synergy between the transporters and the CASP family. In CRC cells, treated with ETC-1922159, these were found to be UP regulated. The engine alotted high numerical valued ranks to some of the 2nd order combinations between the members of the two families. Table 12 and Table 13 show the rankings of ABC transporters w.r.t CASP and vice versa. In Table 12, we found ABC-C5 to be up regulated w.r.t CASP4. These are reflected in rankings of 2495 (laplace) and 2257 (rbf) for CASP4 - ABC-C5. ABC-C5 was up regulated w.r.t CASP5. These are reflected in rankings of 2475 (laplace) and 2234 (rbf) for CASP5 - ABC-C5. ABC-A5/C13/D1 were up regulated w.r.t CASP7. These are reflected in rankings of 2515 (laplace) and 1742 (linear) for CASP7 - ABC-C5; 2489 (laplace) and 2418 (linear) for CASP7 - ABC-C13; and 2323 (laplace) and 2004 (linear) for CASP7 - ABC-D1. ABC-B11/C5/D1/G1 were up regulated w.r.t CASP9. These are reflected in rankings of 2001 (linear) and 2051 (rbf) for CASP9 - ABC-B11; 2180 (laplace) and 2343 (linear) for CASP9 - ABC-C5; 2267 (laplace) and 2382 (rbf) for CASP9 - ABC-C13; 1890 (linear) and 2286 (rbf) for CASP9 - ABC-G1; ABC-A5/C13 were up regulated w.r.t CASP10. These are reflected in rankings of 2292 (laplace), 2311 (linear) and 1108 (rbf) for CASP10 - ABC-A5; 2139 (laplace) and 2203 (linear) for CASP10 - ABC-C13; In Table 13, we found ABC-C5 to be up regulated w.r.t CASP4. These are reflected in rankings of 2495 (laplace) and 2257 (rbf) for CASP4 - ABC-C5. ABC-C5 was up regulated w.r.t CASP5. These are reflected in rankings of 2475 (laplace) and 2234 (rbf) for CASP5 - ABC-C5. ABC-A5/C13/D1 were up regulated w.r.t CASP7. These are reflected in rankings of 2515 (laplace) and 1742 (linear) for CASP7 - ABC-C5; 2489 (laplace) and 2418 (linear) for CASP7 - ABC-C13; and 2323 (laplace) and 2004 (linear) for CASP7 - ABC-D1. ABC-B11/C5/D1/G1 were up regulated w.r.t CASP9. These are reflected in rankings of 2001 (linear) and 2051 (rbf) for CASP9 - ABC-B11; 2180 (laplace) and 2343 (linear) for CASP9 - ABC-C5; 2267 (laplace) and 2382 (rbf) for CASP9 - ABC-C13; 1890 (linear) and 2286 (rbf) for CASP9 - ABC-G1; ABC-A5/C13 were up regulated w.r.t CASP10. These are reflected in rankings of 2292 (laplace), 2311 (linear) and 1108 (rbf) for CASP10 - ABC-A5; 2139 (laplace) and 2203 (linear) for CASP10 - ABC-C13; In Table 13, we found CASP4 to be up regulated w.r.t ABC-D1. These are reflected in rankings of 1791 (laplace) and 1954 (rbf) for CASP4 - ABC-D1. CASP5 was up regulated w.r.t ABC-C13. These are reflected in rankings of 2286 (laplace) and 1905 (rbf) for CASP5 - ABC-C13. CASP7 was up regulated w.r.t ABC-C5. This is reflected in rankings of 2168 (laplace), 1881 (linear) and 2016 (rbf) for CASP7 - ABC-C5. CASP9 were up regulated w.r.t ABC-C5/C13/D1/G1. These are reflected in rankings of 2404 (laplace) and 2374 (linear) for CASP9 - ABC-A5; 2449 (laplace) and 2506 (rbf) for CASP9 - ABC-C13; 1858 (laplace) and 2430 (rbf) for CASP9 - ABC-D1; and 2342 (linear) and 2468 (rbf) for CASP9 - ABC-G1; CASP16 were up regulated w.r.t ABC-A5. This is reflected in rankings of 2477 (linear) and 2315 (rbf) for CASP16 - ABC-A5. Table 14 shows the derived influences which can be represented graphically, with the following influences - • ABC w.r.t CASP with CASP-4 − > ABC-C5; CASP-5 − > ABC-C5; CASP-7 − > ABC-A5/C13/D1; CASP-9 − > ABC-B11/C5/D1/G1; CASP-10 − > ABC-A5/C13; and • CASP w.r.t ABC with CASP-4 < − ABC-D1; CASP-5 < − ABC-C13; CASP-7 < − ABC-C5; CASP-9 < − ABC-C5/C13/D1/G1; CASP-16 < − ABC-A5;

Conclusion

Presented here are a range of multiple synergistic ABC transporter 2nd order combinations that were ranked via a search engine. Later, two way cross family analysis between components of these combinations were conducted. Via majority voting across the ranking methods, it was possible to find plausible unexplored synergistic combinations that might be prevalent in CRC cells after treatment with ETC-1922159 drug. The two-way cross family analysis also assists in deriving influences between components which serve as hypotheses for further tests. If found true, it paves way for biologists/oncologists to further investigate and understand the mechanism behind the synergy through wet experiments.

Author Contributions

Concept, design, in silico implementation - SS. Analysis and interpretation of results - SS. Manuscript writing - SS. Manuscript revision - SS. Approval of manuscript - SS

Data Availability Statement

Data used in this research work was released in a publication in Madan et al. [15]. The ETC-1922159 was released in Singapore in July 2015 under the flagship of the Agency for Science, Technology and Research (A*STAR) and Duke-National University of Singapore Graduate Medical School (Duke-NUS).

Acknowledgments

Special thanks to Mrs. Rita Sinha and Mr. Prabhat Sinha for supporting the author financially, without which this work could not have been made possible.

Conflicts of Interest

There are no conflicts to declare.

References

  1. Sinha, S. Inchoative Discovery of Plausible (Un)explored Synergistic Combinatorial Biological Hypotheses for Static/Time Series Wnt Measurements via Ranking Search Engine : BioSearch Engine Design. Preprints 2018. [Google Scholar]
  2. Sinha, S. Sensitivity analysis based ranking reveals unknown biological hypotheses for down regulated genes in time buffer during administration of PORCN-WNT inhibitor ETC-1922159 in CRC. bioRxiv 2017, 180927. [Google Scholar]
  3. Sinha, S. Prioritizing 2nd order interactions via support vector ranking using sensitivity indices on time series Wnt measurements. bioRxiv 2017, 060228. [Google Scholar]
  4. Joachims, T. Training linear SVMs in linear time. In Proceedings of the 12th ACM SIGKDD international conference on Knowledge discovery and data mining; ACM, 2006; pp. 217–226. [Google Scholar]
  5. Zhou, X.; Engel, T.; Goepfert, C.; Erren, M.; Assmann, G.; von Eckardstein, A. The ATP binding cassette transporter A1 contributes to the secretion of interleukin 1β from macrophages but not from monocytes. Biochemical and biophysical research communications 2002, 291, 598–604. [Google Scholar] [CrossRef] [PubMed]
  6. Haskó, G.; Deitch, E.A.; Németh, Z.H.; Kuhel, D.G.; Szabó, C. Inhibitors of ATP-binding cassette transporters suppress interleukin-12 p40 production and major histocompatibility complex II up-regulation in macrophages. Journal of Pharmacology and Experimental Therapeutics 2002, 301, 103–110. [Google Scholar] [CrossRef] [PubMed]
  7. Park, S.Y.; Han, J.; Kim, J.B.; Yang, M.G.; Kim, Y.J.; Lim, H.J.; An, S.Y.; Kim, J.H. Interleukin-8 is related to poor chemotherapeutic response and tumourigenicity in hepatocellular carcinoma. European Journal of Cancer 2014, 50, 341–350. [Google Scholar] [CrossRef] [PubMed]
  8. Marty, V.; Médina, C.; Combe, C.; Parnet, P.; Amédée, T. ATP binding cassette transporter ABC1 is required for the release of interleukin-1β by P2X7-stimulated and lipopolysaccharide-primed mouse Schwann cells. Glia 2005, 49, 511–519. [Google Scholar] [CrossRef] [PubMed]
  9. Lottaz, D.; Beleznay, Z.; Bickel, M. Inhibition of ATP-binding cassette transporter downregulates interleukin-1β-mediated autocrine activation of human dermal fibroblasts. Journal of investigative dermatology 2001, 117, 871–876. [Google Scholar] [CrossRef] [PubMed]
  10. Ruzickova, E.; Janska, R.; Dolezel, P.; Mlejnek, P. Clinically relevant interactions of anti-apoptotic Bcl-2 protein inhibitors with ABC transporters. Die Pharmazie-An International Journal of Pharmaceutical Sciences 2017, 72, 751–758. [Google Scholar]
  11. Alla, V.; Kowtharapu, B.S.; Engelmann, D.; Emmrich, S.; Schmitz, U.; Steder, M.; Pützer, B.M. E2F1 confers anticancer drug resistance by targeting ABC transporter family members and Bcl-2 via the p73/DNp73-miR-205 circuitry. Cell cycle 2012, 11, 3067–3078. [Google Scholar] [CrossRef] [PubMed]
  12. Yasui, K.; Mihara, S.; Zhao, C.; Okamoto, H.; Saito-Ohara, F.; Tomida, A.; Funato, T.; Yokomizo, A.; Naito, S.; Imoto, I.; others. Alteration in copy numbers of genes as a mechanism for acquired drug resistance. Cancer research 2004, 64, 1403–1410. [Google Scholar] [CrossRef] [PubMed]
  13. Hu, H.; Wang, M.; Guan, X.; Yuan, Z.; Liu, Z.; Zou, C.; Wang, G.; Gao, X.; Wang, X. Loss of ABCB4 attenuates the caspase-dependent apoptosis regulating resistance to 5-Fu in colorectal cancer. Bioscience reports 2018, 38, BSR20171428. [Google Scholar] [CrossRef] [PubMed]
  14. Ihlefeld, K.; Vienken, H.; Claas, R.F.; Blankenbach, K.; Rudowski, A.; Ter Braak, M.; Koch, A.; Van Veldhoven, P.P.; Pfeilschifter, J.; zu Heringdorf, D.M. Upregulation of ABC transporters contributes to chemoresistance of sphingosine 1-phosphate lyase-deficient fibroblasts. Journal of lipid research 2015, 56, 60–69. [Google Scholar] [CrossRef] [PubMed]
  15. Madan, B.; Ke, Z.; Harmston, N.; Ho, S.Y.; Frois, A.; Alam, J.; Jeyaraj, D.A.; Pendharkar, V.; Ghosh, K.; Virshup, I.H.; others. Wnt addiction of genetically defined cancers reversed by PORCN inhibition. Oncogene 2016, 35, 2197. [Google Scholar] [CrossRef] [PubMed]
Table 1. 2nd order interaction ranking between ABC w.r.t UBE2 family members.
Table 1. 2nd order interaction ranking between ABC w.r.t UBE2 family members.
Ranking ABC family w.r.t UBE2 family
Ranking of ABC family w.r.t UBE2-A Ranking of ABC family w.r.t UBE2-B
laplace linear rbf laplace linear rbf
ABC-A5 - UBE2-A 2101 185 382 ABC-A5 - UBE2-B 1223 1193 194
ABC-B11 - UBE2-A 129 2487 304 ABC-B11 - UBE2-B 125 103 571
ABC-C3 - UBE2-A 2137 2491 1023 ABC-C3 - UBE2-B 606 791 1411
ABC-C5 - UBE2-A 1630 490 2408 ABC-C5 - UBE2-B 1515 2317 2266
ABC-C13 - UBE2-A 742 1604 475 ABC-C13 - UBE2-B 2199 2254 2362
ABC-D1 - UBE2-A 316 620 596 ABC-D1 - UBE2-B 1082 374 1057
ABC-G1 - UBE2-A 46 819 533 ABC-G1 - UBE2-B 48 843 551
ABC-G2 - UBE2-A 398 259 261 ABC-G2 - UBE2-B 189 189 41
Ranking of ABC family w.r.t UBE2-F Ranking of ABC family w.r.t UBE2-H
laplace linear rbf laplace linear rbf
ABC-A5 - UBE2-F 997 2408 1784 ABC-A5 - UBE2-H 1247 2068 2438
ABC-B11 - UBE2-F 141 1122 578 ABC-B11 - UBE2-H 932 429 409
ABC-C3 - UBE2-F 931 2420 681 ABC-C3 - UBE2-H 540 1962 563
ABC-C5 - UBE2-F 628 1373 217 ABC-C5 - UBE2-H 1551 865 1450
ABC-C13 - UBE2-F 403 2464 1307 ABC-C13 - UBE2-H 1192 2492 2051
ABC-D1 - UBE2-F 2069 1959 1235 ABC-D1 - UBE2-H 1094 1016 1474
ABC-G1 - UBE2-F 209 1216 1450 ABC-G1 - UBE2-H 683 173 18
ABC-G2 - UBE2-F 690 1995 2120 ABC-G2 - UBE2-H 1328 1374 78
Ranking of ABC family w.r.t UBE2-J1 Ranking of ABC family w.r.t UBE2-Z
laplace linear rbf laplace linear rbf
ABC-A5 - UBE2-J1 634 222 711 ABC-A5 - UBE2-Z 454 1059 1287
ABC-B11 - UBE2-J1 1182 1075 403 ABC-B11 - UBE2-Z 134 503 436
ABC-C3 - UBE2-J1 1232 719 1285 ABC-C3 - UBE2-Z 975 1722 2095
ABC-C5 - UBE2-J1 964 1342 2373 ABC-C5 - UBE2-Z 2348 845 1859
ABC-C13 - UBE2-J1 2095 2412 2360 ABC-C13 - UBE2-Z 1157 651 1335
ABC-D1 - UBE2-J1 542 1198 704 ABC-D1 - UBE2-Z 392 1660 943
ABC-G1 - UBE2-J1 306 97 122 ABC-G1 - UBE2-Z 545 142 354
ABC-G2 - UBE2-J1 335 668 591 ABC-G2 - UBE2-Z 747 285 530
Table 2. 2nd order interaction ranking between UBE2 w.r.t ABC family members.
Table 2. 2nd order interaction ranking between UBE2 w.r.t ABC family members.
Ranking UBE2 family w.r.t ABC family
Ranking of UBE2-A w.r.t ABC Ranking of UBE2-B w.r.t ABC family
laplace linear rbf laplace linear rbf
ABC-A5 - UBE2-A 1037 253 2091 ABC-A5 - UBE2-B 1846 2038 936
ABC-B11 - UBE2-A 1491 1269 2179 ABC-B11 - UBE2-B 1623 1304 1995
ABC-C3 - UBE2-A 1726 1906 1390 ABC-C3 - UBE2-B 1999 832 2050
ABC-C5 - UBE2-A 880 2122 2297 ABC-C5 - UBE2-B 612 2276 1681
ABC-C13 - UBE2-A 412 234 670 ABC-C13 - UBE2-B 467 1863 2496
ABC-D1 - UBE2-A 2507 237 1319 ABC-D1 - UBE2-B 2322 1917 2426
ABC-G1 - UBE2-A 907 2291 1573 ABC-G1 - UBE2-B 1194 1592 1239
ABC-G2 - UBE2-A 2048 1829 1376 ABC-G2 - UBE2-B 1833 2445 2506
Ranking of UNE2-F w.r.t ABC family Ranking of UBE2-H w.r.t ABC family
laplace linear rbf laplace linear rbf
ABC-A5 - UBE2-F 2485 406 66 ABC-A5 - UBE2-H 508 2339 1110
ABC-B11 - UBE2-F 2003 1203 2422 ABC-B11 - UBE2-H 1950 1770 2461
ABC-C3 - UBE2-F 2132 2163 861 ABC-C3 - UBE2-H 2439 1972 2305
ABC-C5 - UBE2-F 406 1651 1838 ABC-C5 - UBE2-H 398 2473 2355
ABC-C13 - UBE2-F 821 959 1196 ABC-C13 - UBE2-H 2004 2317 1847
ABC-D1 - UBE2-F 2421 686 2176 ABC-D1 - UBE2-H 164 1641 648
ABC-G1 - UBE2-F 115 2202 1953 ABC-G1 - UBE2-H 201 1921 2288
ABC-G2 - UBE2-F 983 883 1012 ABC-G2 - UBE2-H 2063 1631 1354
Ranking of UBE2-J1 w.r.t ABC family Ranking of UBE2-Z w.r.t ABC family
laplace linear rbf laplace linear rbf
ABC-A5 - UBE2-J1 1740 1467 1244 ABC-A5 - UBE2-Z 2336 1710 35
ABC-B11 - UBE2-J1 1806 991 1935 ABC-B11 - UBE2-Z 521 645 2168
ABC-C3 - UBE2-J1 2073 2291 631 ABC-C3 - UBE2-Z 1978 1823 1859
ABC-C5 - UBE2-J1 126 525 1409 ABC-C5 - UBE2-Z 1237 148 1928
ABC-C13 - UBE2-J1 2329 2153 1951 ABC-C13 - UBE2-Z 1185 137 2475
ABC-D1 - UBE2-J1 2263 1886 2249 ABC-D1 - UBE2-Z 2292 21 2381
ABC-G1 - UBE2-J1 1262 2418 2277 ABC-G1 - UBE2-Z 426 2515 1858
ABC-G2 - UBE2-J1 1558 2408 1304 ABC-G2 - UBE2-Z 2270 2080 2448
Table 3. 2nd order combinatorial hypotheses between ABC and UBE2.
Table 3. 2nd order combinatorial hypotheses between ABC and UBE2.
Unexplored combinatorial hypotheses
ABC w.r.t UBE2
ABC-C3 UBE2-A
ABC-C5 UBE2-B
ABC-A5/D1/G2 UBE2-F
ABC-A5/C13 UBE2-H
ABC-C13 UBE2-J1
ABC-C5 UBE2-Z
UBE2 w.r.t ABC
UBEA-2 ABC-C5/G2
UBE2-B ABC-A5/C3/C13/D1/G2
UBE2-F ABC-B11/C3/D1/G1
UBE2-H ABC-B11/C3/C5/C13/G1
UBE2-J1 ABC-B11/C3/C13/D1/G1/G2
UBE2-Z ABC-C3/D1/G1/G2
Table 4. 2nd order interaction ranking between ABC family members.
Table 4. 2nd order interaction ranking between ABC family members.
Ranking ABC family w.r.t ABC family
Ranking of ABC family w.r.t ABC-A5 Ranking of ABC family w.r.t ABC-B11
laplace linear rbf laplace linear rbf
ABC-B11 - ABC-A5 733 471 26 ABC-A5 - ABC-B11 1148 1443 1782
ABC-C3 - ABC-A5 111 493 2264 ABC-C3 - ABC-B11 845 527 1257
ABC-C5 - ABC-A5 1717 519 1921 ABC-C5 - ABC-B11 2226 1644 2241
ABC-C13 - ABC-A5 1243 1943 2151 ABC-C13 - ABC-B11 1971 609 2150
ABC-D1 - ABC-A5 1262 2387 1573 ABC-D1 - ABC-B11 891 217 854
ABC-G1 - ABC-A5 657 991 533 ABC-G1 - ABC-B11 1957 1920 669
ABC-G2 - ABC-A5 587 397 104 ABC-G2 - ABC-B11 685 1978 226
Ranking of ABC family w.r.t ABC-C3 Ranking of ABC family w.r.t ABC-C5
laplace linear rbf laplace linear rbf
ABC-A5 - ABC-C3 163 861 1672 ABC-A5 - ABC-C5 2086 411 1243
ABC-B11 - ABC-C3 410 613 1501 ABC-B11 - ABC-C5 2398 272 464
ABC-C5 - ABC-C3 1591 2435 927 ABC-C3 - ABC-C5 2084 2274 1758
ABC-C13 - ABC-C3 405 880 1282 ABC-C13 - ABC-C5 226 2476 2446
ABC-D1 - ABC-C3 18 1145 2187 ABC-D1 - ABC-C5 2010 891 1257
ABC-G1 - ABC-C3 1858 173 842 ABC-G1 - ABC-C5 2402 894 741
ABC-G2 - ABC-C3 1462 275 1373 ABC-G2 - ABC-C5 2463 736 661
Ranking of ABC family w.r.t ABC-C13 Ranking of ABC family w.r.t ABC-D1
laplace linear rbf laplace linear rbf
ABC-A5 - ABC-C13 2251 1219 1614 ABC-A5 - ABC-D1 163 1068 291
ABC-B11 - ABC-C13 1106 56 1171 ABC-B11 - ABC-D1 1273 130 1655
ABC-C3 - ABC-C13 2279 1431 365 ABC-C3 - ABC-D1 568 251 149
ABC-C5 - ABC-C13 1537 2178 690 ABC-C5 - ABC-D1 2423 538 2388
ABC-D1 - ABC-C13 2370 171 362 ABC-C13 - ABC-D1 2383 2029 425
ABC-G1 - ABC-C13 833 1544 1343 ABC-G1 - ABC-D1 1462 1175 827
ABC-G2 - ABC-C13 329 1323 1755 ABC-G2 - ABC-D1 467 670 2491
Ranking of ABC family w.r.t ABC-G1 Ranking of ABC family w.r.t ABC-G2
laplace linear rbf laplace linear rbf
ABC-A5 - ABC-G1 2488 1776 1078 ABC-A5 - ABC-G2 1011 1640 1705
ABC-B11 - ABC-G1 2312 253 52 ABC-B11 - ABC-G2 988 481 1849
ABC-C3 - ABC-G1 273 1415 1139 ABC-C3 - ABC-G2 1102 1082 1563
ABC-C5 - ABC-G1 220 1988 437 ABC-C5 - ABC-G2 2284 1904 1829
ABC-C13 - ABC-G1 2389 427 1125 ABC-C13 - ABC-G2 929 1238 222
ABC-D1 - ABC-G1 1836 485 597 ABC-D1 - ABC-G2 814 995 1152
ABC-G2 - ABC-G1 2506 692 1143 ABC-G1 - ABC-G2 596 460 848
Table 5. 2nd order combinatorial hypotheses between ABC family members.
Table 5. 2nd order combinatorial hypotheses between ABC family members.
Unexplored combinatorial hypotheses
ABC intra family
ABC-C13 ABC-A5
ABC-C5/C13/G1 ABC-B11
ABC-C3/C13 ABC-C5
ABC-C5/C13 ABC-D1
ABC-A5 ABC-G1
ABC-C5 ABC-G2
Table 6. 2nd order interaction ranking between ABC and IL family members.
Table 6. 2nd order interaction ranking between ABC and IL family members.
Ranking ABC family VS IL family
Ranking of IL family w.r.t ABCA5 Ranking of ABCA5 family w.r.t IL
laplace linear rbf laplace linear rbf
IL1A - ABCA5 705 95 11 IL1A - ABCA5 677 2069 871
IL1B - ABCA5 240 35 353 IL1B - ABCA5 2069 790 2301
IL1RAP - ABCA5 1515 2354 514 IL1RAP - ABCA5 1763 335 2345
IL1RN - ABCA5 771 1093 1417 IL1RN - ABCA5 892 2252 1482
IL2RG - ABCA5 500 246 173 IL2RG - ABCA5 993 750 1745
IL6ST - ABCA5 2464 1564 1365 IL6ST - ABCA5 155 266 1386
IL8 - ABCA5 1676 1568 1111 IL8 - ABCA5 104 1261 946
IL10RB - ABCA5 492 146 643 IL10RB - ABCA5 2230 2184 2240
IL15 - ABCA5 638 1169 65 IL15 - ABCA5 661 169 711
IL15RA - ABCA5 2151 1672 740 IL15RA - ABCA5 706 1300 2031
IL17C - ABCA5 680 197 164 IL17C - ABCA5 615 575 1518
IL17REL - ABCA5 1014 2405 2202 IL17REL - ABCA5 212 1024 146
Ranking of IL family w.r.t ABCB11 Ranking of ABCB11 family w.r.t IL
laplace linear rbf laplace linear rbf
IL1A - ABCB11 1962 465 648 IL1A - ABCB11 551 140 385
IL1B - ABCB11 1778 851 438 IL1B - ABCB11 255 428 208
IL1RAP - ABCB11 1427 1704 1318 IL1RAP - ABCB11 1681 878 1709
IL1RN - ABCB11 1832 539 297 IL1RN - ABCB11 342 1912 779
IL2RG - ABCB11 2182 2102 550 IL2RG - ABCB11 814 67 584
IL6ST - ABCB11 1793 2140 1938 IL6ST - ABCB11 1347 1504 385
IL8 - ABCB11 1607 2441 1028 IL8 - ABCB11 349 846 1786
IL10RB - ABCB11 341 1119 449 IL10RB - ABCB11 2101 2419 1352
IL15 - ABCB11 2438 2512 576 IL15 - ABCB11 344 224 256
IL15RA - ABCB11 2271 1288 1784 IL15RA - ABCB11 1052 48 719
IL17C - ABCB11 1262 69 706 IL17C - ABCB11 653 316 437
IL17REL - ABCB11 50 305 783 IL17REL - ABCB11 1004 736 896
Ranking of IL family w.r.t ABCC3 Ranking of ABCC3 family w.r.t IL
laplace linear rbf laplace linear rbf
IL1A - ABCC3 1860 758 1538 IL1A - ABCC3 1343 1798 2459
IL1B - ABCC3 1764 749 896 IL1B - ABCC3 1647 1369 569
IL1RAP - ABCC3 1514 2294 1989 IL1RAP - ABCC3 2074 1377 303
IL1RN - ABCC3 647 607 1252 IL1RN - ABCC3 1366 975 1354
IL2RG - ABCC3 990 444 40 IL2RG - ABCC3 1229 379 844
IL6ST - ABCC3 98 1589 339 IL6ST - ABCC3 970 712 1342
IL8 - ABCC3 1767 1046 2419 IL8 - ABCC3 937 1033 430
IL10RB - ABCC3 1354 78 359 IL10RB - ABCC3 1609 29 1830
IL15 - ABCC3 1580 602 1560 IL15 - ABCC3 1087 1191 1084
IL15RA - ABCC3 189 2403 1795 IL15RA - ABCC3 2153 163 1324
IL17C - ABCC3 1587 778 2425 IL17C - ABCC3 466 631 2237
IL17REL - ABCC3 1135 403 54 IL17REL - ABCC3 2089 2388 1618
Ranking of IL family w.r.t ABCC5 Ranking of ABCC5 family w.r.t IL
laplace linear rbf laplace linear rbf
IL1A - ABCC5 2004 681 60 IL1A - ABCC5 2217 2022 1512
IL1B - ABCC5 1948 112 251 IL1B - ABCC5 1223 2137 942
IL1RAP - ABCC5 1038 355 2023 IL1RAP - ABCC5 1982 1892 2296
IL1RN - ABCC5 709 430 1087 IL1RN - ABCC5 1668 816 2142
IL2RG - ABCC5 1421 264 601 IL2RG - ABCC5 500 2018 1691
IL6ST - ABCC5 1569 2010 845 IL6ST - ABCC5 754 2326 874
IL8 - ABCC5 1869 143 1589 IL8 - ABCC5 855 1211 2434
IL10RB - ABCC5 1162 70 434 IL10RB - ABCC5 1337 736 958
IL15 - ABCC5 1262 147 389 IL15 - ABCC5 1947 1991 1584
IL15RA - ABCC5 1083 2255 1861 IL15RA - ABCC5 2457 1444 534
IL17C - ABCC5 2447 96 116 IL17C - ABCC5 1836 845 1802
IL17REL - ABCC5 54 2462 2509 IL17REL - ABCC5 1247 2149 1031
Table 7. 2nd order interaction ranking between ABC and IL family members.
Table 7. 2nd order interaction ranking between ABC and IL family members.
Ranking ABC family VS IL family
Ranking of IL family w.r.t ABCC13 Ranking of ABCC13 family w.r.t IL
laplace linear rbf laplace linear rbf
IL1A - ABCC13 512 135 1207 IL1A - ABCC13 464 352 201
IL1B - ABCC13 152 103 1553 IL1B - ABCC13 635 974 60
IL1RAP - ABCC13 1092 502 2442 IL1RAP - ABCC13 2136 2392 33
IL1RN - ABCC13 1753 559 323 IL1RN - ABCC13 114 1016 1839
IL2RG - ABCC13 2064 674 1076 IL2RG - ABCC13 807 1079 938
IL6ST - ABCC13 332 1416 2112 IL6ST - ABCC13 119 1098 2323
IL8 - ABCC13 551 1200 1680 IL8 - ABCC13 592 984 907
IL10RB - ABCC13 631 621 561 IL10RB - ABCC13 2011 1272 1297
IL15 - ABCC13 502 296 373 IL15 - ABCC13 612 968 170
IL15RA - ABCC13 2248 1955 2456 IL15RA - ABCC13 2397 2485 790
IL17C - ABCC13 25 140 123 IL17C - ABCC13 924 308 711
IL17REL - ABCC13 2339 2137 1497 IL17REL - ABCC13 462 376 461
Ranking of IL family w.r.t ABCC5 Ranking of ABCC5 family w.r.t IL
laplace linear rbf laplace linear rbf
IL1A - ABCD1 1932 30 2203 IL1A - ABCD1 530 2046 1196
IL1B - ABCD1 569 109 1778 IL1B - ABCD1 1400 605 453
IL1RAP - ABCD1 2508 2006 1907 IL1RAP - ABCD1 399 840 1548
IL1RN - ABCD1 606 2003 789 IL1RN - ABCD1 551 2025 60
IL2RG - ABCD1 1064 284 2374 IL2RG - ABCD1 311 1233 1322
IL6ST - ABCD1 1347 1237 1220 IL6ST - ABCD1 1581 507 612
IL8 - ABCD1 2010 2315 1814 IL8 - ABCD1 2501 2154 539
IL10RB - ABCD1 631 825 85 IL10RB - ABCD1 1795 1028 2325
IL15 - ABCD1 890 325 1578 IL15 - ABCD1 1795 302 1258
IL15RA - ABCD1 2097 1765 1629 IL15RA - ABCD1 580 1240 2342
IL17C - ABCD1 1372 56 2509 IL17C - ABCD1 687 1753 851
IL17REL - ABCD1 5 2388 237 IL17REL - ABCD1 1423 642 2164
Ranking of IL family w.r.t ABCG1 Ranking of ABCG1 family w.r.t IL
laplace linear rbf laplace linear rbf
IL1A - ABCG1 724 67 80 IL1A - ABCG1 699 824 600
IL1B - ABCG1 938 178 533 IL1B - ABCG1 70 783 81
IL1RAP - ABCG1 1263 2205 2339 IL1RAP - ABCG1 2298 394 612
IL1RN - ABCG1 1240 688 1396 IL1RN - ABCG1 2465 834 1051
IL2RG - ABCG1 1396 7 112 IL2RG - ABCG1 587 24 21
IL6ST - ABCG1 357 845 520 IL6ST - ABCG1 1723 1345 177
IL8 - ABCG1 977 1835 1099 IL8 - ABCG1 1730 1748 382
IL10RB - ABCG1 2244 349 840 IL10RB - ABCG1 167 1315 61
IL15 - ABCG1 1960 613 1279 IL15 - ABCG1 2212 734 326
IL15RA - ABCG1 785 651 2191 IL15RA - ABCG1 1195 862 1876
IL17C - ABCG1 2516 486 51 IL17C - ABCG1 80 95 177
IL17REL - ABCG1 2229 732 150 IL17REL - ABCG1 1579 1025 452
Ranking of IL family w.r.t ABCG2 Ranking of ABCG2 family w.r.t IL
laplace linear rbf laplace linear rbf
IL1A - ABCG2 745 716 1299 IL1A - ABCG2 238 89 659
IL1B - ABCG2 354 232 668 IL1B - ABCG2 31 197 439
IL1RAP - ABCG2 2184 2167 1384 IL1RAP - ABCG2 1314 253 2434
IL1RN - ABCG2 783 228 11 IL1RN - ABCG2 552 1692 827
IL2RG - ABCG2 444 463 1024 IL2RG - ABCG2 261 87 1275
IL6ST - ABCG2 1647 1827 55 IL6ST - ABCG2 1792 1477 1222
IL8 - ABCG2 2212 1362 563 IL8 - ABCG2 448 441 1423
IL10RB - ABCG2 31 80 667 IL10RB - ABCG2 2144 2335 2434
IL15 - ABCG2 76 312 187 IL15 - ABCG2 247 590 832
IL15RA - ABCG2 1910 2428 1921 IL15RA - ABCG2 1116 1005 1059
IL17C - ABCG2 649 692 61 IL17C - ABCG2 784 462 775
IL17REL - ABCG2 883 1435 35 IL17REL - ABCG2 852 1606 1597
Table 8. 2nd order combinatorial hypotheses between ABC and IL family members.
Table 8. 2nd order combinatorial hypotheses between ABC and IL family members.
Unexplored combinatorial hypotheses
ABC w.r.t IL
IL-1B/1RAP/10RB ABCA5
IL-10RB ABCB11
IL-1A/17REL ABCC3
IL-1A/1RAP/15/17C ABCC5
IL-1RAP/15RA ABCC13
IL-8/10RB ABCD1
IL-10RB ABCG2
IL w.r.t ABC
IL-17REL ABCA5
IL-2RG/6ST/15/15RA ABCB11
IL-8/15RA ABCC3
IL-15RA/17REL ABCC5
IL-15RA/17REL ABCC13
IL-1A/1RAP/8/15RA ABCD1
IL-1RAP ABCG1
IL-1RAP/15RA ABCG2
Table 9. 2nd order interaction ranking between BCL and ABC family members.
Table 9. 2nd order interaction ranking between BCL and ABC family members.
Ranking BCL family VS ABC family
Ranking of BCL2L1 w.r.t ABC family Ranking of ABC family w.r.t BCL2L1
laplace linear rbf laplace linear rbf
ABCA5 - BCL2L1 18 560 1715 ABCA5 - BCL2L1 1522 220 1818
ABCB11 - BCL2L1 1124 2418 552 ABCB11 - BCL2L1 2002 234 10
ABCC3 - BCL2L1 564 394 64 ABCC3 - BCL2L1 2085 2309 929
ABCC5 - BCL2L1 2239 1845 823 ABCC5 - BCL2L1 599 847 1282
ABCC13 - BCL2L1 805 1590 2407 ABCC13 - BCL2L1 744 616 614
ABCD1 - BCL2L1 356 202 930 ABCD1 - BCL2L1 839 352 195
ABCG1 - BCL2L1 793 2005 885 ABCG1 - BCL2L1 1249 265 1165
ABCG2 - BCL2L1 199 99 906 ABCG2 - BCL2L1 401 620 277
Ranking of BCL2L2 w.r.t ABC family Ranking of ABC family w.r.t BCL2L2
laplace linear rbf laplace linear rbf
ABCA5 - BCL2L2 1476 324 1792 ABCA5 - BCL2L2 174 482 501
ABCB11 - BCL2L2 2097 1311 2311 ABCB11 - BCL2L2 148 380 1204
ABCC3 - BCL2L2 1091 1569 259 ABCC3 - BCL2L2 890 949 1398
ABCC5 - BCL2L2 2195 2359 2322 ABCC5 - BCL2L2 765 1875 736
ABCC13 - BCL2L2 2438 2494 898 ABCC13 - BCL2L2 2271 1436 1665
ABCD1 - BCL2L2 2477 831 2156 ABCD1 - BCL2L2 1432 1291 64
ABCG1 - BCL2L2 352 1653 2234 ABCG1 - BCL2L2 406 1206 966
ABCG2 - BCL2L2 1515 2409 1496 ABCG2 - BCL2L2 404 314 55
Ranking of BCL2L13 w.r.t ABC family Ranking of ABC family w.r.t BCL2L13
laplace linear rbf laplace linear rbf
ABCA5 - BCL2L13 1398 202 2292 ABCA5 - BCL2L13 655 951 1380
ABCB11 - BCL2L13 2505 261 1855 ABCB11 - BCL2L13 1579 53 224
ABCC3 - BCL2L13 1642 1769 1334 ABCC3 - BCL2L13 265 588 459
ABCC5 - BCL2L13 1427 1835 2178 ABCC5 - BCL2L13 1975 2421 927
ABCC13 - BCL2L13 2484 2184 2410 ABCC13 - BCL2L13 1894 2335 2475
ABCD1 - BCL2L13 2472 1579 2201 ABCD1 - BCL2L13 912 511 1041
ABCG1 - BCL2L13 3 2276 2095 ABCG1 - BCL2L13 957 649 488
ABCG2 - BCL2L13 2172 1723 1502 ABCG2 - BCL2L13 2142 392 1206
Ranking of BCL3 w.r.t ABC family Ranking of ABC family w.r.t BCL3
laplace linear rbf laplace linear rbf
ABCA5 - BCL3 940 45 777 ABCA5 - BCL3 960 1354 2477
ABCB11 - BCL3 260 1002 483 ABCB11 - BCL3 731 1483 2028
ABCC3 - BCL3 2101 214 304 ABCC3 - BCL3 1782 2186 1251
ABCC5 - BCL3 1155 775 1176 ABCC5 - BCL3 2192 957 280
ABCC13 - BCL3 270 1116 1619 ABCC13 - BCL3 1725 1407 1747
ABCD1 - BCL3 759 2194 2106 ABCD1 - BCL3 836 811 1359
ABCG1 - BCL3 2014 1559 2253 ABCG1 - BCL3 550 247 247
ABCG2 - BCL3 480 465 1949 ABCG2 - BCL3 792 798 1418
Table 10. 2nd order interaction ranking between ABC and BCL family members.
Table 10. 2nd order interaction ranking between ABC and BCL family members.
Ranking BCL family VS ABC family
Ranking of BCL6 w.r.t ABC family Ranking of ABC family w.r.t BCL6
laplace linear rbf laplace linear rbf
ABCA5 - BCL6 2045 557 1384 ABCA5 - BCL6 211 283 1615
ABCB11 - BCL6 1611 2010 2350 ABCB11 - BCL6 841 427 2320
ABCC3 - BCL6 1895 983 958 ABCC3 - BCL6 1084 570 594
ABCC5 - BCL6 615 597 567 ABCC5 - BCL6 1370 1841 2389
ABCC13 - BCL6 1097 2431 1731 ABCC13 - BCL6 2172 2456 1063
ABCD1 - BCL6 1446 1139 1953 ABCD1 - BCL6 1097 1297 827
ABCG1 - BCL6 1462 1688 1918 ABCG1 - BCL6 192 27 1111
ABCG2 - BCL6 947 1503 978 ABCG2 - BCL6 129 745 719
Ranking of BCL9L w.r.t ABC family Ranking of ABC family w.r.t BCL9L
laplace linear rbf laplace linear rbf
ABCA5 - BCL9L 67 1008 94 ABCA5 - BCL9L 1753 1167 2312
ABCB11 - BCL9L 1989 158 1705 ABCB11 - BCL9L 1033 494 48
ABCC3 - BCL9L 1307 2249 1357 ABCC3 - BCL9L 457 2296 971
ABCC5 - BCL9L 1694 432 477 ABCC5 - BCL9L 1775 1551 2073
ABCC13 - BCL9L 1724 1410 862 ABCC13 - BCL9L 110 2475 2325
ABCD1 - BCL9L 1366 2344 1666 ABCD1 - BCL9L 1016 2440 2411
ABCG1 - BCL9L 1248 1680 536 ABCG1 - BCL9L 1146 676 16
ABCG2 - BCL9L 2451 1119 224 ABCG2 - BCL9L 1263 1421 218
Ranking of BCL10 w.r.t ABC family Ranking of ABC family w.r.t BCL10
laplace linear rbf laplace linear rbf
ABCA5 - BCL10 687 176 808 ABCA5 - BCL10 1753 1167 2312
ABCB11 - BCL10 2234 2382 322 ABCB11 - BCL10 1033 494 48
ABCC3 - BCL10 589 379 492 ABCC3 - BCL10 457 2296 971
ABCC5 - BCL10 1489 397 1643 ABCC5 - BCL10 1775 1551 2073
ABCC13 - BCL10 956 538 1491 ABCC13 - BCL10 110 2475 2325
ABCD1 - BCL10 1009 470 1597 ABCD1 - BCL10 1016 2440 2411
ABCG1 - BCL10 1613 310 1115 ABCG1 - BCL10 1146 676 16
ABCG2 - BCL10 361 676 2020 ABCG2 - BCL10 1263 1421 218
Table 11. 2nd order combinatorial hypotheses between BCL and ABC family members.
Table 11. 2nd order combinatorial hypotheses between BCL and ABC family members.
Unexplored combinatorial hypotheses
BCL w.r.t ABC
ABC-C5 BCL2L1
ABC-B11/C5/C13/D1 BCL2L2
ABC-B11/C5/C13/D1/G1 BCL2L13
ABC-D1/G1 BCL3
ABC-B11 BCL6
ABC-B11 BCL10
ABC w.r.t BCL
ABC-C3 BCL2L1
ABC-C5/C13 BCL2L13
ABC-C3 BCL3
ABC-C5/C13 BCL6
ABC-C5/C13/D1 BCL9L
ABC-A5/C5/C13/D1 BCL10
Table 12. 2nd order interaction ranking between ABC and CASP family members.
Table 12. 2nd order interaction ranking between ABC and CASP family members.
Ranking ABC family w.r.t CASP family
Ranking of ABC family w.r.t CASP4 Ranking of ABC family w.r.t CASP5
laplace linear rbf laplace linear rbf
CASP4 - ABC-A5 957 682 991 CASP5 - ABC-A5 733 1986 421
CASP4 - ABC-B11 19 727 158 CASP5 - ABC-B11 513 406 355
CASP4 - ABC-C3 1242 857 1848 CASP5 - ABC-C3 685 1694 1558
CASP4 - ABC-C5 2495 1316 2257 CASP5 - ABC-C5 2475 1038 2234
CASP4 - ABC-C13 154 1537 1206 CASP5 - ABC-C13 1660 1581 853
CASP4 - ABC-D1 1494 964 999 CASP5 - ABC-D1 354 725 1304
CASP4 - ABC-G1 1405 70 326 CASP5 - ABC-G1 298 485 382
CASP4 - ABC-G2 157 176 523 CASP5 - ABC-G2 706 846 1598
Ranking of ABC family w.r.t CASP7 Ranking of ABC family w.r.t CASP9
laplace linear rbf laplace linear rbf
CASP7 - ABC-A5 2515 1742 25 CASP9 - ABC-A5 1125 1863 694
CASP7 - ABC-B11 1299 207 348 CASP9 - ABC-B11 729 2001 2051
CASP7 - ABC-C3 992 511 2222 CASP9 - ABC-C3 1108 1470 1465
CASP7 - ABC-C5 1232 1449 2154 CASP9 - ABC-C5 2180 2343 1732
CASP7 - ABC-C13 2489 2418 1623 CASP9 - ABC-C13 2267 1472 2382
CASP7 - ABC-D1 1544 2323 2004 CASP9 - ABC-D1 1011 1086 174
CASP7 - ABC-G1 665 382 670 CASP9 - ABC-G1 580 1890 2286
CASP7 - ABC-G2 1930 23 963 CASP9 - ABC-G2 647 2374 310
Ranking of ABC family w.r.t CASP10 Ranking of ABC family w.r.t CASP16
laplace linear rbf laplace linear rbf
CASP10 - ABC-A5 2292 2311 1108 CASP16 - ABC-A5 165 408 113
CASP10 - ABC-B11 2245 1467 1182 CASP16 - ABC-B11 495 949 1417
CASP10 - ABC-C3 760 2479 923 CASP16 - ABC-C3 50 4 556
CASP10 - ABC-C5 326 485 1429 CASP16 - ABC-C5 1635 2487 1309
CASP10 - ABC-C13 2139 2203 1524 CASP16 - ABC-C13 1517 936 1236
CASP10 - ABC-D1 2210 475 1655 CASP16 - ABC-D1 1029 1210 1285
CASP10 - ABC-G1 2337 128 71 CASP16 - ABC-G1 350 756 109
CASP10 - ABC-G2 2075 1693 1306 CASP16 - ABC-G2 318 476 515
Table 13. 2nd order interaction ranking between CASP and ABC family members.
Table 13. 2nd order interaction ranking between CASP and ABC family members.
Ranking CASP family w.r.t ABC family
Ranking of CASP4 w.r.t ABC family Ranking of CASP5 w.r.t ABC family
laplace linear rbf laplace linear rbf
CASP4 - ABC-A5 791 586 753 CASP5 - ABC-A5 696 427 48
CASP4 - ABC-B11 462 263 427 CASP5 - ABC-B11 1470 1300 242
CASP4 - ABC-C3 1013 54 1140 CASP5 - ABC-C3 821 286 459
CASP4 - ABC-C5 2396 26 209 CASP5 - ABC-C5 2368 665 171
CASP4 - ABC-C13 1305 775 2193 CASP5 - ABC-C13 2286 739 1905
CASP4 - ABC-D1 1791 591 1954 CASP5 - ABC-D1 653 440 972
CASP4 - ABC-G1 593 99 173 CASP5 - ABC-G1 2176 446 317
CASP4 - ABC-G2 423 109 1364 CASP5 - ABC-G2 332 122 533
Ranking of CASP7 w.r.t ABC family Ranking of CASP9 w.r.t ABC family
laplace linear rbf laplace linear rbf
CASP7 - ABC-A5 1726 697 1874 CASP9 - ABC-A5 2404 2374 1265
CASP7 - ABC-B11 1549 189 1692 CASP9 - ABC-B11 998 1258 2046
CASP7 - ABC-C3 2331 1572 69 CASP9 - ABC-C3 1398 2358 1445
CASP7 - ABC-C5 2168 1881 2016 CASP9 - ABC-C5 1023 965 1080
CASP7 - ABC-C13 1822 865 1239 CASP9 - ABC-C13 2449 1545 2506
CASP7 - ABC-D1 111 813 2230 CASP9 - ABC-D1 1858 2430 412
CASP7 - ABC-G1 1609 983 1994 CASP9 - ABC-G1 305 2342 2468
CASP7 - ABC-G2 1094 952 102 CASP9 - ABC-G2 1868 1621 1154
Ranking of CASP10 w.r.t ABC family Ranking of CASP16 w.r.t ABC family
laplace linear rbf laplace linear rbf
CASP10 - ABC-A5 683 1453 1437 CASP16 - ABC-A5 960 2477 2315
CASP10 - ABC-B11 1301 774 558 CASP16 - ABC-B11 402 1860 794
CASP10 - ABC-C3 369 683 1453 CASP16 - ABC-C3 171 825 23
CASP10 - ABC-C5 1823 346 761 CASP16 - ABC-C5 2467 585 258
CASP10 - ABC-C13 1320 832 868 CASP16 - ABC-C13 428 177 64
CASP10 - ABC-D1 249 1440 387 CASP16 - ABC-D1 651 153 2010
CASP10 - ABC-G1 1687 1232 156 CASP16 - ABC-G1 2398 421 1120
CASP10 - ABC-G2 1151 651 464 CASP16 - ABC-G2 1193 734 479
Table 14. 2nd order combinatorial hypotheses between BCL and ABC family members.
Table 14. 2nd order combinatorial hypotheses between BCL and ABC family members.
Unexplored combinatorial hypotheses
ABC w.r.t CASP
CASP-4 ABC-C5
CASP-5 ABC-C5
CASP-7 ABC-A5/C13/D1
CASP-9 ABC-B11/C5/D1/G1
CASP-10 ABC-A5/C13
CASP w.r.t ABC
CASP-4 ABC-D1
CASP-5 ABC-C13
CASP-7 ABC-C5
CASP-9 ABC-C5/C13/D1/G1
CASP-16 ABC-A5
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
Copyright: This open access article is published under a Creative Commons CC BY 4.0 license, which permit the free download, distribution, and reuse, provided that the author and preprint are cited in any reuse.
Prerpints.org logo

Preprints.org is a free preprint server supported by MDPI in Basel, Switzerland.

facebook logotwitter logolinkedin logo
MDPI Initiatives
Important Links
Subscribe

Disclaimer

Terms of Use

Privacy Policy

© 2024 MDPI (Basel, Switzerland) unless otherwise stated