Autophagy is an important metabolic pathway to determine leukemia cell survival following suppression of the glycolytic pathway.

Most cancer cells predominantly produce energy by glycolysis, even in the presence of adequate oxygen. Therefore, inhibition of glycolysis is a promising cancer treatment target. Recently, it has been recognized that to conduct thorough treatment of cancer, comprehensive understanding of cancer metabolism is essential, not only focusing on glycolysis. Here, we investigated the supporting mechanism of autophagy, which is a catabolic process that recycles intracellular components, for energy supply in the glycolysis-inhibited condition. Autophagy is thought to be highly activated in cancers and to promote their growth or progression by adapting to the harsh surrounding microenvironment. We found that cancer cells positively promoted autophagy to overcome the energy shortage from glycolysis by maintaining mitochondrial activity for ATP production essential for survival. Conclusively, autophagy plays a role in determining whether cancer cells live or die, and autophagic ability in cancer cells is a promising target for therapy.

Shift in energy metabolism caused by glucocorticoids enhances the effect of cytotoxic anti-cancer drugs against acute lymphoblastic leukemia cells.

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Treatments include glucocorticoids (GCs) such as dexamethasone (Dex) and prednisolone, which may be of value when used alongside cytotoxic anti-cancer drugs. To predict therapeutic efficacy of GCs, their activity against ALL cells is usually examined prior to chemotherapy; however, few studies have examined their effects when used in combination with other drugs. The paradox is that cytotoxic anti-cancer drugs that are effective against proliferating cancer cells show synergistic effects when used with GCs that prevent cell proliferation. To address this point, we investigated intracellular energy metabolism in ALL CCRF-CEM cell clones classified according to their sensitivity to Dex and cytotoxic anti-cancer drugs in bulk cultures of mixed cells. We found that Dex suppressed glycolysis, the most important metabolic system in cancer cells, in cells that were damaged by etoposide (a cytotoxic anti-cancer drug), and the cells showed a concomitant increase in mitochondrial oxidative phosphorylation. Furthermore, autophagy, an intracellular bulk degradation system, regulated mitochondrial viability. We also found that mitochondria, whose function is enhanced by Dex, were susceptible to anti-cancer drugs that inhibit respiratory complexes (e.g., etoposide and daunorubicin), resulting in increased production of reactive oxygen species and subsequent cytotoxicity. Taken together, the present study points the way toward a more accurate prediction of the sensitivity of ALL cells to the combined action of anti-cancer drugs and GCs, by taking into consideration the shift in intracellular energy metabolism caused by GCs: namely, from glycolysis to mitochondrial oxidative phosphorylation mediated by autophagy.