This metabolism toward aerobic glycolysis thus enhancing lactate

This complex role which autophagy plays in cancer cells also affects and complicates cancer treatment response. The role of autophagy differs depending on tumor stage (early/late) and cell type and/or genetic factors. It seems to be tumor suppressive during cancer development but promotes cancer survival during cancer progression. Therefore the autophagy pathways can be either activated or inhibited with different anti-cancer drugs with varying results.  (Kyong Sook Choi)

Cancer cells are addicted to glycolytic pathway because of the energetic profits it provides, but other than that it enables them to gather a certain pool of intermediate metabolites to perform biosynthetic reactions. This makes glucose pathway disruption an attractive point which therapeutic substances should target. Therefore because of cancer cell sensitivity to glucose shortage, once this occurs autophagy is upregulated, (Goldsmith J) and excessive upregulation risks the induction of autophagic cell death. Targeting glycolysis is the exact effect that Verapamil most likely has on cancer cells in which it stimulates autophagy by switching metabolism toward aerobic glycolysis thus enhancing lactate production although the exact mechanism is still under research. (Kania E., B. Paj?k).

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These metabolic alterations (aerobic glycolysis and enhanced autophagy) are as described earlier a feature associated with tumor progression. In established tumor especially, metabolic stress arising from e.g. insufficient nutrients, oxygen or increased energetic demands of proliferation induces autophagy while these cells search for alternative source of energy. (Onodera and Oshumi). To further explore the relationship between autophagy and cell death, a research has shown that cancerous cells (COLO 205) after treatment with verapamil and inducing autophagy, were challenged with the autophagy inhibitor chloroquine, an approved anti-malarian chemotherapeutic which is a lysosomotropic agent that by raising lysosomal pH prevents endosomal acidification (like Sodium oxamate). Verapamil alone induced cell death shown by PARP and caspase 3 cleaved forms. The extent of this cleavage was even greater when verapamil was administrated together with CQ. To confirm, autophagy was inhibited by disrupting the autophagy genes ATG5 or ATG7 in the COLO205 cells using CRISPR/cas9. (Minor levels of the ATG5-12 complex was still visible after deletion). Higher levels of PARP were discovered in ATG-gene deleted cells compared to normal control cells. It was concluded that verapamil does not require functional autophagy to mediate its cytotoxic effects and that autophagy actually involved in limiting verapamil-induced cytotoxicity in those cells. Verapamil induces cytoprotective autophagy, which if inhibited either at the later stages of autophagy by CQ, or at the initiation of autophagy by ATG5 and ATG7 gene deletion, leads to enhanced cell death in those cells. (Kania E., B. Paj?k).

Apart from the main hypothesis in our study we were additionally interested to know how much ATG5 and ATG7 proteins are actually involved in autophagy, and how deleting them would have a great effect on autophagy inhibition. What we know about these proteins is as follows; The conjugation of ATG12 to ATG5 starts with activation by ATG7 (homolog of E1 ubiquitin-activating enzyme). ATG7 hydrolyzes ATP resulting in the activation of ATG12. ATG12 is then transferred to the active site cysteine of ATG19, which catalyzes the conjugation of ATG12 to ATG5 forming an isopeptide bond. ATG5-ATG12 is finally assembled with ATG16 forming a tetramer. This complex called an omegasome (shaped like the Greek letter capital omega ?), is involved in autophagosome formation, specifically early stages, the vesicle nucleation. (Walczak,). The omegasome is a site from which phagophores form and expand to house the cargo of interest until the omegasome closes then fuses with the lysosome forming the autophagosome. The mechanism by which the autophagosome detaches from the omegasome is not clear.( Uemura T, )


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