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A peer-reviewed article of this preprint also exists.
supplementary.xlsx (64.24KB )
This version is not peer-reviewed
Submitted:
12 December 2023
Posted:
13 December 2023
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Gene | Encoding DNA | Protein | Cycle | Reported dysregulation in cancer | Publications |
---|---|---|---|---|---|
Aco2 | Nuclear | Aconitase 2 | TCA (Krebs cycle) |
|
[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 |
|
[72,76,98,99,100,101,102,103,104,105,106] |
FH | Nuclear | Fumarate Hydratase | TCA |
|
[73,76,107,108,109,110,111] |
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 |
|
Evade apoptosis | [113,115,116] |
P53 | Tumor Suppressor gene | Point mutation, Deletion | P53 pathway, Cell Cycle Control: G2/M DNA Damage Checkpoint |
|
Evade apoptosis, insensitivity to anti-growth signals | [113,117,118] |
PI3K (Phophatidylinositol-4,5-Bisphosphate 3-Kinase) |
Tumor Suppressor | Point mutation | AKT pathway |
|
Evade apoptosis | [113,119] |
PTEN (Phosphatase and Tensin Homolog) |
Tumor Suppressor | Point mutation, deletion | PI3K pathway |
|
Evade apoptosis | [113,120] |
MDM2 (Mouse Double Minute 2, Human Homolog Of; P53-Binding Protein) |
Oncogenes | Amplification | Cell Cycle Control: G1/S Checkpoint |
|
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] |
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] |
Flavonoid’s name | Flavonoid subfamily | Mechanism of targeting Warburg glycolysis | Warburg glycolytic target | References |
---|---|---|---|---|
Apegenin | Flavones |
|
PKM2 | [322] |
epigallocatechin-3-gallate (EGCG) | Flavan-3-ols |
|
PKM2 | [323] |
|
HK2 HIF-1a |
[323] [323] |
||
Proanthocyanidin B2 (PB2) | Anthocyanidins |
|
PKM2 | [324] |
Shikonin (SHI) | Naphthoquinone flavonoid |
|
PKM2 | [325,326] |
Quercetin (QUE) | Flavonol |
|
PKM2 | [327] |
|
HK2 | [327] | ||
|
LDH | [327] | ||
Xanthohumol (XA) | Prenylated Flavonoid |
|
HK2 | [328] |
10v | Synthetic flavonoid |
|
HK2 | [329] |
GL-V9 | Synthetic flavonoid |
|
HK2 | [330] |
FV-429 | Synthetic flavonoid |
|
HK2 | [331] |
Gen-27 | Synthetic flavonoid |
|
HK2 | [332] |
Astragalin (ASG) | O-glycoside flavonoid |
|
HK2 | [333] |
Morin (MO) | Flavonol |
|
LDH | [334] |
Methylalpinumisoflavon (MF) | Isoflavone |
|
HIF-1α | [335] |
Oroxylin A (OX-A) | Flavone |
|
HIF-1α | [336] |
Baicalein (BA) | Flavone |
|
HIF-1α | [337] |
Wogonin | O-methylated flavone |
|
HIF-1α | [338] [339] |
Berberine (BBR) | Isoquinoline flavonoid |
|
HK2 | [340] [341] |
Resveratrol |
|
HK2 PDH complex |
[342] [343] [344] |
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