Utilizing the Warburg Effect to Enhance TRAIL-Induced Apoptosis in Several Cancer Types

A study was conducted investigating the therapeutic potential of exploiting metabolic reprogramming of cancer cells for sensitization to an extrinsic mediator of apoptosis using both mechanistic and pre-clinical experiments. Specifically, we studied the effects of 2-Deoxy-D-Glucose (2DG) on TNF-Related Apoptosis-Inducing Ligand (TRAIL)-induced apoptosis in TRAIL-resistant cancer cell lines. Co-treatment with 2DG+TRAIL was found to cause dramatic synergy in apoptosis with little to no effect on normal cells. Treatment with 2DG results in modulation of TRAIL cognate receptors. Death Receptor 5 (DR5) transcript, protein and cell surface expression were elevated with 2DG treatment with no effect on other TRAIL receptors. Enhanced DR5 expression correlated with enhanced activation of the extrinsic apoptotic pathway, though abrogation of DR5 expression was not sufficient to prevent 2DG+TRAIL synergy. Other cellular effects of 2DG+TRAIL were found using both NanoString-based microRNA screening and kinase inhibitor screening. These studies found that miR-494 was synergistically upregulated with 2DG+TRAIL treatment and was sufficient to confer TRAIL sensitivity. In addition, MEK inhibitors could completely inhibit the effect of 2DG+TRAIL. Taken together with prior reports that MEK signaling regulates miR-494 expression, this data suggests an important role of MEK signaling in mediating the effect of 2DG+TRAIL. The precise mechanism of miR-494 sensitization to TRAIL is currently under investigation. Therapeutic efficacy of 2DG+TRAIL was investigated using a hind limb xenograft mouse model. Untreated mice or those given TRAIL alone demonstrated aggressive increase in tumor burden over five days. 2DG alone, however caused significant attenuation of tumor growth. However, only the combination treatment caused 15% tumor regression of established solid tumors. This work provides new insights into sensitivity of cancer cells to TRAIL-induced apoptosis as well as a novel therapeutic strategy that may be broadly applicable to multiple cancer types due to the hallmark of metabolic reprogramming.