1. Introduction

2. The Metabolic Shift in Cancer

2.1. Why Do Tumors Adopt Glycolysis over OXPHOS?

Both anaerobic glycolysis and OXPHOS produce cellular energy in the form of adenosine triphosphate (ATP). OXPHOS is much more efficient in generating ATP than glycolysis; it generates approximately 32 ATPs from a single glucose molecule, whereas glycolysis produces only a net of two ATPs (see Figure 1). Briefly, during glycolysis, a single molecule of glucose is converted into two molecules of pyruvate through a series of biochemical reactions that ultimately result in the production of two ATPs, after consuming two ATPs in the glycolytic process. The resultant pyruvate can either enter the Krebs cycle (tricarboxylic acid (TCA) cycle) followed by OXPHOS in the mitochondria in aerobic conditions or it can be converted to lactate in anaerobic conditions. OXPHOS is an oxygen-dependent process that combines the oxidation of nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH₂) with the phosphorylation of ADP to form ATP. In contrast, in anaerobic glycolysis, the conversion of pyruvate to lactate consumes NAD⁺ to generate NADH. The biochemical landscapes of glycolysis, aerobic glycolysis, and the TCA cycle have been well reviewed by Akram in 2013 [60,61]. Another recent review by Shiva et al. (2020) elegantly describes OXPHOS, which is also known as the electron transport chain (ETC) cycle [62]. The selection of a less efficient metabolic pathway by the cell is attributed to the fast-track generation of ATP by glycolysis, when compared to OXPHOS. Therefore, it was believed that an increase in the rate of aerobic glycolysis would promptly deliver the energy needs of the cell [22,63,64,65,66]. In that sense, an increase in the frequency of aerobic glycolysis translates into an increase in glucose uptake [67] and rapid ATP synthesis. However, this explanation was found to be insufficient to justify the glycolytic surge in tumors even in the presence of functional mitochondria. There are other reasons and theories that emerged, which are discussed in the following sections (see Figure 2). It is worth pointing out that another theory of altered energy metabolism in tumor cells exists and is termed the reverse Warburg effect or tumor symbiosis. This theory highlights a crosstalk between hypoxic tumor cells and normoxic stromal cells, in which the stromal cells take up the lactate generated by the hypoxic tumor cells and use it as fuel to generate ATP via oxidative mechanisms. The ATP generated by normoxic cells then becomes a source of energy for the neighboring hypoxic tumor cells [68]. This lactate shuttle and the interplay between the heterogenic metabolic phenotypes in the core and microenvironment of the tumor assist in the survival of tumor cells [68,69,70,71].

In the next subsections, we summarize the reasons behind the adoption of glycolysis over OXPHOS in tumor cells.

2.1.1. Reason 1: Mitochondrial Dysfunction

Despite controversies around the presence of functional or partially functional mitochondria in some cancers, we believe these observations are an exception rather than the standard. Discovering signs of mitochondrial activity in some cancer phenotypes does not equate to the presence of normally functional mitochondria. Mitochondrial dysfunction continues to be the leading cause of predominantly occurring glycolysis over OXPHOS in tumor cells. Several mechanisms contribute to the development of mitochondrial dysfunction in tumor cells (see Figure 3); this is fortified by the mutations or transcriptomic dysregulations found in the genes that encode OXPHOS- and glycolysis-related proteins (Table 1 and Table 2).

OXPHOS-related genes are either of mitochondrial DNA (mtDNA) or nuclear DNA (ncDNA) origin. Point mutations are the most common type of mutations in mtDNA reported to date. Even more interesting are the mutations occurring in oncogenes and tumor suppressor genes, which are frequent and characteristic to all cancer types. Many oncogenes and tumor suppressor genes indirectly regulate glycolysis and OXPHOS by regulating the expression of OXPHOS-related or glycolytic proteins (Table 3). Moreover, mitochondrial metabolic dysfunction in cancer can also result from the dysregulation of mitochondrial biogenesis and mitophagy. Regarding cancer, there are other mutations in ncDNA genes that encode TCA cycle-related enzymes, such as succinate dehydrogenase (SDH) [72], fumarate hydratase (FH) [73], and isocitrate dehydrogenase (IDH) [74,75], which have a direct effect on OXPHOS [76] (Table 1). For instance, Bourgeron et al. reported — for the first time —that a mutation in the SDH gene caused mitochondrial ETC deficiency [77]. In 2018, Böttcher et al. discovered that a gain-of-function mutation in IDH leads to enhanced D-2HG production, which triggers the destabilization of the hypoxia-inducible factor-1 alpha (HIF-1α) protein, thus making the cell more dependent on OXPHOS [78].

Likewise, tumorigenic mutations in cardinal oncogenes and tumor suppressor genes significantly contribute to mitochondrial dysfunction in cancer. Although oncogenes and tumor suppressor genes do not directly encode OXPHOS-related or glycolytic proteins, they indirectly regulate the activity of these proteins through cell signaling pathways (Table 2). This strongly abates the rationale claiming the presence of functional mitochondrial OXPHOS in cancer. Common oncogenes and tumor suppressor genes involved in the mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), and mammalian target of rapamycin (mTOR) pathways have been heavily reported in most cancer types and can affect mitochondrial function (Table 2).

Mitochondrial deregulation is also manifested by an imbalance in the degree of biogenesis of mitochondrial organelles and mitophagy of unhealthy mitochondria. Imbalances in mitochondrial organelle turnover results in an abnormal number of available mitochondrial organelles in the cytoplasm, which have been implicated in cancer progression [79,80]. Autophagy is inhibited by mTOR pathway activity. An active AMP-activated protein kinase (AMPK) pathway inhibits the mTOR pathway, thereby activating autophagy. Autophagy promotes cell survival by recycling cellular organelles to produce energy. Reportedly, there is an association between high autophagic activity and increased cancer resistance to chemotherapy [81,82]. Mitophagy, on the other hand, degrades mitochondria through either the PTEN induced kinase 1 (PINK1)/Parkin (PRKN) or the BCL2 interacting protein 3 (BNIP3)/NIP-3-like protein X (NIX)/FUN14 domain containing 1 (FUNDC1) pathways, or by AMPK activation and consequent phosphorylation of Unc-51 like autophagy activating kinase 1 (ULK1). Interestingly, some studies have shown that the downregulation of PRKN causes a decrease in mitophagy and the accumulation of dysfunctional mitochondria in the cytoplasm. This has been associated with decreased mitochondrial OXPHOS, increased ROS, and increased glycolysis. Therefore, PRKN deficiency contributes towards the Warburg effect in cancer. PRKN deficiency has been observed in several cancer phenotypes in humans, including colorectal cancer [83], glioblastoma [84], melanoma [85], lung cancer [86], and breast cancer [79,87].

Some studies have suggested that the overexpression of uncoupling protein (UCP) promotes aerobic glycolysis, tumor proliferation, and resistance to apoptosis-induced chemotherapy [88,89,90]. UCPs are a family of mitochondrial proteins localized in the mitochondrial membrane that act as anion transporters. UCP2, in particular, is ubiquitously expressed in the body and plays several biological functions and has been shown to play a role in both tumorigenesis and chemoresistance. UCP2 has an antioxidant effect due to its role in transporting protons from the inner mitochondrial membrane to the inner mitochondrial matrix [91]. In 2016, Brandi et al. demonstrated that UCP2 caused the downregulation of OXPHOS-related Complex I (NADH dehydrogenase), Complex IV (cytochrome c oxidase), Complex V (ATPase), and a decrease in mitochondrial oxygen consumption [90].

Table 1. Common alterations in the genes involved in the TCA cycle and OXPHOS metabolism in cancer.

Table 1. Common alterations in the genes involved in the TCA cycle and OXPHOS metabolism in cancer.

Gene	Encoding DNA	Protein	Cycle	Reported dysregulation in cancer	Publications
Aco2	Nuclear	Aconitase 2	TCA (Krebs cycle)	Overexpression Increased activity	[76,92]
IDH1	Nuclear	Isocitrate Dehydrogenase 1	TCA	Point mutations	[74,76,93,94,95,96,97]
SDH	Nuclear	Succinate Dehydrogenase	TCA and ETC cycle	Inherited or somatic mutations in the SDH Downregulation	[72,76,98,99,100,101,102,103,104,105,106]
FH	Nuclear	Fumarate Hydratase	TCA	Germline mutations. Reduced FH gene expression	[73,76,107,108,109,110,111]

Table 2. Common oncogenes and tumor suppressor genes implicated in mitochondrial dysfunction in cancer.

Table 2. Common oncogenes and tumor suppressor genes implicated in mitochondrial dysfunction in cancer.

Gene	Class	Genetic alteration	Pathway affected	Effects on OXPHOS (ETC cycle)	The effect of cancer progression	References
MYC (MYC proto-Oncogene Protein)	Oncogene	Point mutation, amplification	TGF-β Signaling Pathway	Stimulates mitochondrial biogenesis and function through regulating Transcription Factor A Mitochondrial gene	Self-sufficiency in growth status	[76,112,113,114]
AKT (Alpha Serine/Threonine Kinase)	Oncogene	Point mutation, amplification, overexpression	AKT pathway	Affects mitochondria membrane potential (DWmt). Activated PI3-K–AKT pathway enhances mitochondrial membrane stability by inhibition of p53 and Bax expression to limit mitochondria-associated apoptosis. Stimulates the glycolysis pathway. PTEN inactivation upregulates mitochondrial respiratory capacity through the 4E-BP1-mediated protein translation pathway.	Evade apoptosis	[113,115,116]
P53	Tumor Suppressor gene	Point mutation, Deletion	P53 pathway, Cell Cycle Control: G2/M DNA Damage Checkpoint	P53 downregulation blocks its transcriptional activity and its localization to mitochondria, thus inhibiting mitochondrial-mediated apoptosis and enhancing mitochondrial DNA (mtDNA) mutagenesis. P53 downregulation reduces SCO2 gene expression and cytochrome-c to molecular oxygen, thus maintaining the proton gradient across the inner mitochondrial membrane that is necessary for aerobic ATP production.	Evade apoptosis, insensitivity to anti-growth signals	[113,117,118]
PI3K (Phophatidylinositol-4,5-Bisphosphate 3-Kinase)	Tumor Suppressor	Point mutation	AKT pathway	Downregulation of PI3K activates and upregulates AKT signaling and mTOR downstream transcription of p70 which regulate the transcription of key apoptosis- regulatory proteins. Decrease in mitochondrial membrane potential. Decrease in the release of Cytochrome-c into the cytoplasm. Prevent activation of the proapoptotic caspase family of proteins does not get activated.	Evade apoptosis	[113,119]
PTEN (Phosphatase and Tensin Homolog)	Tumor Suppressor	Point mutation, deletion	PI3K pathway	PTEN downregulation activates PI3-K–AKT pathway. Decrease mitochondrial membrane stability by inhibition of the proapoptotic proteins p53 and Bax expression to limit mitochondria-associated apoptosis (intrinsic pathway).	Evade apoptosis	[113,120]
MDM2 (Mouse Double Minute 2, Human Homolog Of; P53-Binding Protein)	Oncogenes	Amplification	Cell Cycle Control: G1/S Checkpoint	Negatively regulates NADH: ubiquinone oxidoreductase, 75 kDa Fe-S protein 1 (NDUFS1) and NADH dehydrogenase 6 (MT-ND6) involves the d in the ETC cycle. MDM2 overexpression decreases the function and efficiency of mitochondrial Complex I (CI).	Evade apoptosis	[113,121]
BRAF (B-Raf Proto-Oncogene, Serine/Threonine Kinase)	Oncogenes	Point mutation, amplification, increased expression	MAPK pathway (RAS)	BRAF upregulation inhibits oxidative phosphorylation gene transcription, mitochondrial b, biogenesis, and the expression of PGC1a by targeting the melanocyte lineage factor (MITF).	Self-sufficiency in growth status	[113,122]
KRAS (Kirsten rat sarcoma viral oncogene homolog, GTPase)	Oncogene	Point mutation	MAPK pathway	KRAS activation of MAPK and PI3K pathways stabilizes and activates hypoxia-inducible factors-1 alpha and -2 alpha (HIF-1α and HIF-2) which facilitates ischemic adaptation. KRAS stimulates aerobic glycolysis by overexpressing Hexokinase, lactate dehydrogenase, and glucose transporters. KRAS induces glutaminolysis by upregualting Glutamate Oxaloacetate Transaminase 1,2. (GOT), leading to aspartate and NADPH generation, and the activation of the NRF2 antioxidant system. Upregulation of RAS leads to increased autophagy and micropinocytosis contributing to the disruption of cellular energy balance and nutrient scavenging.	Self-sufficiency in growth status	[113,123,124,125,126]
NF-κB (Nuclear Factor Kappa B)	Oncogene	Amplification, rearrangement, chromosomal translocation in several members of the NF-κB protein family or constitutional activation of NF-κB	NF-κB pathway	NF-κB upregulation and activity cause a decline in mitochondrial respiratory capacity and reduces the expression of key mitochondrial proteins including SDHA, ANT-1, UCP3, and MFN2 and causes increased fission and mitophagy of mitochondrial organelle. It upregulates PGC1α and correlates with high ROS.	Tumor growth	[113,127,128]
EGFR (ErbB1 Epidermal Growth Factor Receptor)	Oncogene	Amplification, upregulation	PI3K and MAPK pathway	EGFR modulates mitochondrial function through modification of Cox-II	Self-sufficiency in growth status	[113,129]
IGFR (Insulin-like Growth factor receptor)	Oncogene	Amplification	AKT, PI3K, and MAPK pathways	Increased IGFR expression alters ATP synthesis and increases mitochondrial function. And decrease mitochondrial ROS production associated with the induction of antioxidant response.	antiapoptotic, cell-survival, and transforming activities	[113,130]
ErbB2 (HER2, Receptor tyrosine-protein kinase erbB-2 )	Oncogene	Amplification	MAPK, PI3K, AKT, and mTOR	ErbB2 overexpression causes downregulation of pro-apoptotic Bcl-2 family protein (Bcl-xS) and increases levels of anti-apoptotic Bcl-xL. This leads to mitochondrial dysfunction and a loss of mitochondrial membrane potential, a 35% decline in ATP levels, and a loss of redox capacity (mitochondrial reductase activity).	Anti-apoptotic and pro-proliferative effects	[113,131]
HIF-1 α (Hypoxia Inducible Factor 1 Subunit Alpha)	Oncogene	It is stabilized and activated in hypoxic tumor conditions and by inactivating mutations of SDH, FH, IDH as well as due to oncogenic mutation activating other signaling pathways (MAPK, AKT, and mTOR)		HIF-1α induces the expression of pyruvate dehydrogenase kinase 1 (PDK1). PDK1 phosphorylates and inactivates mitochondrial pyruvate dehydrogenase. Enhances the dependence of cells on glycolysis for ATP production instead of OXPHOS.	Metabolism, cell survival, erythropoiesis, angiogenesis	[132,133,134]

2.1.2. Reason 2: Glycolysis Supports the Proliferative Needs of Cancer Cells

In cancer, tumor cells employ strategies that promote their survival, growth, and invasion. Therefore, it has been theorized that cancer cells use aerobic glycolysis as a trade-off because it supports the biosynthetic anabolic needs pertaining to constant, uncontrolled proliferation [67].

The Warburg effect supplies nucleic acids, proteins, and lipids through certain branching pathways that emanate from glycolysis. For instance, the pentose phosphate pathway (PPP) produces the reducing agent NADPH, which is used in de novo lipid synthesis [135,136,137]. Besides, the diversion of the glycolysis flux towards de novo serine biosynthesis is utilized by the enzyme phosphoglycerate dehydrogenase (PHGDH) [67,138]. Additionally, lactate is produced during the final step of anaerobic glycolysis, along with NAD⁺. The produced NAD⁺ acts as a positive feedback mechanism to keep glycolysis active and ensure that the supply chain of building blocks is operating [139]. The produced intracellular lactate is shuttled to the extracellular stroma, giving it its acidic attributes in cancer [140]. An outstanding study by Heiden et al. (2020) revealed that an increased cellular demand for NAD⁺, which is comparably more than the demand for ATP and the rate of ATP turnover, is what drives the preferential dependence on aerobic glycolysis, rather than OXPHOS, in proliferating cells, such as cancer cells [141]. The NAD⁺/NADH ratio is critical for several metabolic processes, including nucleotide synthesis, lipid metabolism, amino acid metabolism, and central carbon metabolism [142]. Redox reactions and biosynthetic processes both require NAD+ generation [141]. NAD+ regeneration by the ETC cycle is constrained due to increased mitochondrial membrane potential and decreased ATP synthase activity during OXPHOS in proliferating cancer cells [141]. Owing to the increased NAD⁺ demand from cancer cells, the cell diverts its metabolic phenotype towards aerobic glycolysis [141].

Undifferentiated stem cells resemble cancer cells in having high proliferative activity, and therefore, they similarly shift their metabolism towards anaerobic glycolysis instead of OXPHOS [143,144]. During stem cell differentiation, cellular metabolism switches back to mitochondrial OXPHOS to generate energy, while the rate of anaerobic glycolysis declines [145]. The dysregulation of the intracellular and extracellular pH of cancer cells that accompanies aerobic glycolysis is another means by which the Warburg effect promotes tumor growth [140]. Dysregulated pH dynamics characterized by extracellular acidic stromal cells and intracellular alkaline cytoplasm are hallmarks of cancer cells and can influence tumor proliferation, metastasis, and metabolic shift [140]. Proliferating cancer cells require an alkaline intracellular pH compared to normal quiescent cells that have an acidic intracellular pH [146,147,148]. The increase in intracellular pH in a cancer cell promotes the glycolytic metabolic shift and confers a proliferative advantage for tumor cells [149,150,151]. For instance, a cytoplasmic alkaline pH is required for growth factors to initiate nucleic acid synthesis [147]. Moreover, an alkaline intracellular pH promotes intracellular protein synthesis and drives other phenotypes of cancer cells [140,152,153].

2.1.3. Reason 3: Activation of HIF-1α by ROS

Another reason for the glycolytic shift in cancer is the accumulation of ROS, which causes the activation of HIF-1α. Usually, in hypoxic conditions, HIF-1α gets activated when the cell senses a low oxygen supply. ROS mimics the hypoxic effect and activates HIF-1α, which then promotes glycolysis by upregulating the expression of several glycolytic enzymes, including hexokinase 2 [154,155], phosphofructokinase [156], phosphoglucomutase 1 [157], enolase [158], pyruvate kinase, pyruvate dehydrogenase (PDH), pyruvate dehydrogenase kinase (PDK) [159], lactate dehydrogenase A (LDHA) [158], monocarboxylate transporter 4 [160,161,162], and glucose transporters, GLUT1 and GLUT3 [163]. Additionally, HIF-1α reduces the OXPHOS capacity by inhibiting mitochondrial biogenesis [164,165], decreasing PDH activity [159], and reducing ETC activity [166].

2.1.4. Reason 4: Dysregulation of the Glycolytic Machinery

Studies have indicated that dysregulation occurs at the level of glycolytic protein expression (Table 3). Subsequent research has elucidated the role of the pyruvate dehydrogenase complex (PDC) in the metabolic switch in tumor cells towards aerobic glycolysis. In 2007, Koukourakis et al. observed a significant decrease or absence of PDC expression and/or an overexpression of PDK in 91% of lung cancer patients tested via immunohistochemistry [7]. Typically, active PDC facilitates the oxidative decarboxylation of pyruvate into acetyl-CoA within the mitochondria. Conversely, PDK phosphorylates and deactivates PDC [15]. When PDC is inactive, pyruvate accumulates in the mitochondria and translocates back to the cytosol, where it is converted to lactate and NADH [15].

In this milieu, NADH was found to play a role in the glycolytic shift by directly or indirectly inhibiting PDC and activating PDK. Recent studies propose that a high concentration of cytosolic NADH, coupled with increased pyruvate, decreased lactate, and an active LDHA enzyme, positively promotes glycolysis in cancer [69,167,168,169].

Certain investigations have also demonstrated that overexpression of the antioxidant UCP2 in cancer cell lines promotes aerobic glycolysis, tumor proliferation, and resistance to apoptosis-induced chemotherapy [88,89,90] (see Figure 2). In 2016, Brandi et al. illustrated that UCP2 upregulates the expression of heterogeneous nuclear ribonucleoprotein A2/B1, which, in turn, regulates the transcription of GLUT1, pyruvate kinase M2 (PKM2), and LDH genes. UCP2 facilitates the metabolic shift in cancer cells towards Warburg's aerobic glycolysis[90].

Table 3. Common alterations reported in glycolysis-related genes in cancer.

Table 3. Common alterations reported in glycolysis-related genes in cancer.

Gene ID	Gene Name	Mutation/deregulation	Function in glycolysis	Publication
HK	Hexokinase	Upregulated by p53 in cancer and promotes tumor growth and survival	Phosphorylates glucose when it enters the cells	[76,170,171,172]
PFK1	6-PhosphoFruktoKinsae-1	Amplification and/or upregulation, posttranslational modification reported in multiple cancer types.	PFK1 catalyzes the phosphorylation of fructose-6-phosphate (F6P) to fructose-1, 6-bisphosphate (Fru-1,6-P2) using Mg-ATP as a phosphoryl donor.	[76,173,174,175]
PK	Pyruvate Kinase	Posttranslational modification or enhanced expression that benefits cancer	PK is involved in the final step of glycolysis, and it mediates the transfer of a phosphate group from phosphoenolpyruvate (PEP) to ADP resulting in pyruvate and ATP.	[76,176,177,178,179]
PDK-1	Pyruvate Dehydrogenase Kinase -1	Upregulation	PDK is a kinase enzyme that inactivates Pyruvate Dehydrogenase by phosphorylation dephosphorylation at different specific serine residues. PDK decreases the oxidation of pyruvate in mitochondria and increases the conversion of pyruvate to lactate in the cytosol.	[76,180,181,182]

2.1.5. Reason 5: AMPK Inhibition in Cancer Leads to a Glycolytic Shift

AMPK is a highly conserved serine/threonine protein complex that acts as a metabolic sensor and a master regulator of cellular metabolic homeostasis [183]. AMPK can be activated by either one of the two cell signals; the first is intracellular Ca²⁺-dependent, while the second is AMP-dependent (see Figure 4). AMPK is modulated either by phosphorylation or allosteric activation. In response to an increase in the AMP/ATP ratio, liver kinase B1 (LKB1) gets activated, which in turn directly activates AMPK by phosphorylation at Thr172, located in the catalytic subunit of the AMPK protein [184,185,186,187]. The AMP/ATP ratio can be altered during various intracellular states, such as hypoxia, glucose deprivation, calcium concentration, cytokines, and adipokines, and by certain hormones [187]. On the one hand, active AMPK inhibits the biosynthetic pathways in the cell, such as hepatic fatty acid synthesis and protein synthesis. On the other hand, active AMPK activates ATP-generating catabolic pathways, such as fatty acid uptake and oxidation, glycolysis, and mitochondrial biogenesis (see Figure 5). In cancer, AMPK is generally considered as a tumor suppressor [188]. Studies found that the dysregulation of AMPK plays a role in the glycolytic metabolic switch in cancer. Low AMPK expression is further implicated in tumorigenesis by promoting tumor initiation and progression [189]. Inactivation or reduced expression of AMPK in cancer promotes tumor growth and invasiveness [190,191]. This is an expected scenario, considering the activities exerted by AMPK.

A closer look at how AMPK shifts the metabolic phenotype in cancer reveals that AMPK modulates mitochondrial respiration through activating autophagy (including mitophagy) by phosphorylating and activating ULK1; this regulates the localization of an important component of the phagophore called autophagy-related protein 9 (ATG9) [192,193] (see Figure 5). mTOR, on the one hand, can inhibit ULK1/2, thus blocking autophagy [194]. AMPK can also induce mitochondrial biogenesis, which aims to increase the capacity of OXPHOS. Moreover, Faubert et al. (2013) found that AMPK negatively regulates the Warburg effect and suppresses tumor growth in vivo [195]. Faubert et al. documented that knocking down the α catalytic subunit of AMPK accelerates Myc-induced tumorigenesis. Moreover, the inactivation of AMPK caused stabilization of HIF-1α and a glycolytic shift in tumor cells in vitro. Altogether, the inhibition of AMPK in cancer inhibits OXPHOS and activates the Warburg effect in tumor cells (see Figure 5).

More interestingly, in cancer, AMPK acts through the AMPK/tuberous sclerosis complex (TSC)/mTOR signaling axis to regulate the metabolic switch. Inoki and colleagues found that active AMPK phosphorylates and activates TSC2 [196]. Earlier, Inoki had established that both TSC1/2 inhibits the activity of mTOR by inhibiting the phosphorylation of ribosomal protein S6 kinase B1 (S6K) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), which are downstream targets of mTOR [196,197]. Inoki et al. further reported that TSC1/2 inhibits the phosphorylation of S6K and 4E-BP1 by targeting Ras homolog (Rheb)− the protein that activates the protein kinase activity of mTOR [198]. Inoki et al. showed that TSC2 acts as a GTPase-activating protein and blocks the activity of Rheb and regulates its levels in vitro [198]. In cancer, mTOR is frequently high and has been found to activate aerobic glycolysis via the induction of pyruvate kinase isoenzyme 2 (PKM2) and other glycolytic enzymes [199]. In a recent study by Ling et al. that showed unprecedented results, mTOR was reported to directly inhibit AMPK via the phosphorylation of AMPK α1, S347 and α2, S345 in mammalians, accompanied with reduced phosphorylation of the activation loop T172. A loss of mTOR activity caused AMPK activation independent of the AMP/ATP ratio [200].

Collectively, active AMPK could activate autophagy either directly through the activation of ULK2 or indirectly by activating TSC 2, which further inhibits mTOR.

3. The Metabolic Shift in T2D

4. Metabolic Therapeutic Approaches in Cancer and T2D

5. Nutritional Therapeutic Approaches in Cancer and T2D

6. Conclusion

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