Glycolysis inhibition sensitizes tumor cells to death receptors-induced apoptosis by AMP kinase activation leading to Mcl-1 block in translation

Abstract

Most cancer cells exhibit increased glycolysis for generation of their energy supply. This specificity could be used to preferentially kill these cells. In this study, we identified the signaling pathway initiated by glycolysis inhibition that results in sensitization to death receptor (DR)-induced apoptosis. We showed, in several human cancer cell lines (such as Jurkat, HeLa, U937), that glucose removal or the use of nonmetabolizable form of glucose (2-deoxyglucose) dramatically enhances apoptosis induced by Fas or by tumor necrosis factor-related apoptosis-inducing ligand. This sensitization is controlled through the adenosine monophosphate (AMP)-activated protein kinase (AMPK), which is the central energy-sensing system of the cell. We established the fact that AMPK is activated upon glycolysis block resulting in mammalian target of rapamycin (mTOR) inhibition leading to Mcl-1 decrease, but no other Bcl-2 anti-apoptotic members. Interestingly, we determined that, upon glycolysis inhibition, the AMPK-mTOR pathway controlled Mcl-1 levels neither through transcriptional nor through posttranslational mechanism but rather by controlling its translation. Therefore, our results show a novel mechanism for the sensitization to DR-induced apoptosis linking glucose metabolism to Mcl-1 downexpression. In addition, this study provides a rationale for the combined use of DR ligands with AMPK activators or mTOR inhibitors in the treatment of human cancers.

Switching from aerobic glycolysis to oxidative phosphorylation modulates the sensitivity of mantle cell lymphoma cells to TRAIL

“…Removal of glucose or inhibition by 2DG is generally believed to produce essentially the same effects on cellular metabolism and sensitivity to apoptotic agents. 29,43 Our study shows that this is not necessarily true for all cell types. In Z138 cells maintained in glucose-free conditions, TRAIL-R1 and -R2 expression were slightly down-regulated and TRAIL-R1 induced DISC formation and activity (IETDase) attenuated (Figures 3a --d), which could in part explain the slower onset of apoptosis (Figure 4c).…”

“…Mcl-1 in particular was significantly depleted in 2DG-treated cells, in agreement with a recent study using other human cancer cell lines. 29 Z138 cells cultured in glucose-free media switch from aerobic glycolysis to oxidative phosphorylation and are less sensitive to TRAIL-induced apoptosis Since 2DG markedly inhibited cellular ATP levels, we investigated whether glucose removal from pyruvate and glutamine supplemented culture media would produce similar effects on metabolism, ATP levels and TRAIL sensitivity. We therefore investigated the effect of glucose deprivation on Z138 cells by switching the cells to glucose-free media supplemented with pyruvate and glutamax (L-alanyl-L-glutamine).…”

Sugar-free approaches to cancer cell killing

“…Rathmell and colleagues demonstrated that enforcement of glycolysis in hematopoietic cells leads to stabilization of Mcl-1 by inhibiting its degradation (Zhao et al, 2007). On the contrary, as discussed above, glucose deprivation or treatment with 2-DG results in AMPK-dependent mTor inactivation; this was shown to inhibit translation of Mcl-1 (Pradelli et al, 2010). Thus, Mcl-1 is controlled at translational and post-translational levels by the glycolytic metabolism.…”

“…However, proteins of the apoptotic extrinsic pathway are very frequently upregulated or downregulated in tumors, and some tumor cells are resistant to low doses of TRAIL. In vitro studies have shown that glucose withdrawal or treatment with 2-DG can overcome resistance to TRAIL, TNF-a and Fas ligation in several cell lines (Nam et al, 2002;Munoz-Pinedo et al, 2003;Pradelli et al, 2010) (Table 2). At the molecular level, these results could be explained, at least in some cell lines, by the effects of glucose levels on the inhibitors of apoptosis FLIP and Mcl-1.…”

Time schedule-dependent effect of the CK2 inhibitor TBB on PC-3 human prostate cancer cell viability

“…Looking for a possible CK2 target that might act as an anti-survival factor we paid attention to the glycolytic enzyme phosphoglucose isomerase. Cell viability is critically dependent on glycolysis because of its direct link to some stages of apoptosis (35)(36)(37)(38)(39) and because of controlling the ATP concentration (35,36). Phosphorylation of phosphoglucose isomerase inhibits its activity and is suggested to be a factor that may influence glucose metabolism in the cancer cells (40).…”