Potential application of Alpha-ketoglutaratefor the treatment of colorectal cancer

Background: Cancer is a disease in which cells in a specificpart of the body divide uncontrollably and invade other parts ofthe body. Alpha-ketoglutarate (AKG) is one of the metabolitesof the tricarboxylic acid (TCA) cycle and synthesized in thebody. It plays a crucial role in cell energy metabolism, aminoacid/protein synthesis, epigenetic regulation, and cancer cellbehaviors. In cancer cells, the glycolysis-related reactions aredisrupted, and then the TCA cycle metabolites are shifted fromthe energy production pathway to produce compounds andmacromolecules needed for cell proliferation, which is a hallmarkof cancer cells. Cancer cells have the ability to convertAKG directly to succinyl-CoA, thereby continue the TCA cycleand then produce NADH and ATP for energy.Main body: AKG inhibits tumor growth through upregulatingH۳/H۴ histone acetylases, Ten-Eleven Translocation ۳ (TET۳)and DNA demethylation in colorectal cancer cells (CRC). AKGalso suppresses Wnt signaling, promotes cell differentiation,and limits tumor growth in CRC patient-derived organoidsand multiple in vivo CRC tumor models. It has been reportedthat combination of dimethyl AKG (dm-AKG) and B۸۷ orother inhibitors of oxidative phosphorylation (OXPHOS) isable to destroy different cancer cell, including human coloncancer cell line (HCT۱۱۶). Their combination cause activationof cell death program through disruption of the mitochondrialnetwork, activation of poly (ADP-ribose) polymerase ۱(PARP۱), apoptosis-inducing factor mitochondrion-associated۱ (AIFM۱), and apurinic/apyrimidinic endo deoxyribonuclease۱ (APEX۱). Moreover, AKG increases the phosphorylationof Mitogen-activated protein kinases (MAPKs), promotes theintrinsic apoptosis signaling pathway, and reduces the level ofHypoxia-inducible factor ۱ (HIF-۱), Transforming growth factorbeta (TGF-β), vascular endothelial growth factor (VEGF),leading to reduce cell proliferation, migration, and metastasis.Conclusion: AKG has a great potential for the treatment ofcolorectal cancer and can use various mechanisms to controlcell proliferation, migration and metastasis

کلیدواژه ها:

Alpha-ketoglutarate ، CRC ، DNA demethylation ، Wnt-signaling