PERK-eIF2alpha-mediated translational inhibition of MCL-1 contributes to potential 2-deoxy-D-glucose and BAD mimetic combinatorial cancer therapy

Glycolysis inhibitor 2-Deoxy-D-glucose (2DG) has been extensively studied as a potential therapeutic agent because tumors depend more on aerobic glycolysis than normal cells for their energy supply. However, the precise mechanism underlying 2DG's toxicity remains not so clear. In this study, we confirmed that 2DG induces Apoptosis primarily by disrupting glycosylation rather than glycolysis. We observed that glucose depletion or 2DG treatment leads to a significant reduction of Mcl-1 protein levels. Further analysis revealed that 2DG toxicity required Mcl-1 degradation. Moreover, BAD was identified as the only BH3-only protein whose single knockout can block 2DG-induced Apoptosis. The downregulation of Mcl-1, combined with the dephosphorylation of BAD at Serine 155, contribute to the simultaneous inactivation of the anti-apoptotic functions of both Mcl-1 and Bcl-xL, which is sufficient to induce 2DG toxicity. Additionally, our experiments showed that Endoplasmic Reticulum (ER) stress induced PERK-eIF2α pathway mediated translational inhibition of Mcl-1 contributes to 2DG toxicity. Based on these findings, the combined use of 2DG with BAD BH3 mimetic have proven effective against various types of Cancer cells. In conclusion, this study provides a theoretical basis and rationale for the combined use of 2DG and BH3 mimetics as a promising therapeutic strategy for cancers.

Apoptosis; BAD; Dephosphorylation; Glycolysis inhibitor; Glycosylation; MCL-1.