Molecular targeting of glutaminase sensitizes ovarian cancer cells to chemotherapy

Altered metabolism is a reemerging hallmark of tumorigenesis. Increased cell proliferation results in metabolic reprogramming to facilitate the needs of the rapidly dividing tumor cells. In addition to increased glucose uptake, tumors also take up increased levels of glutamine. Some cancers develop a reliance on glutamine, and are referred to as "glutamine addicted." These tumors over express the enzyme glutaminase which is involved in the first step of glutaminolysis. The goal of this study was to determine the effects of combined treatment of the glutaminase inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES) with chemotherapy on drug resistant ovarian cancer cells. We found that ovarian cancer cells show different dependencies on exogenous glutamine. However, regardless of glutamine dependence status, treatment with BPTES sensitized both paclitaxel, and cisplatin resistant cancer cell lines to chemotherapy by inhibiting cell proliferation. Monotherapy with BPTES alone resulted in a significant reduction in the ability of glutamine dependent cancer cells to form colonies in a clonogenic assay. In addition, glutamine dependent, metastatic cancer cells expressed higher levels of glutaminase 1 (GLS1) isoforms, KGA and GAC, than untransformed cells. Moreover, dual targeting of both isoforms using siRNA was more effective at sensitizing the cancer cells to cisplatin than targeting either GAC or KGA alone. Our results suggest that both GLS1 isoforms are important for glutamine dependent ovarian cancer survival, hence, both GLS1 isoforms should be targeted for therapy in metastatic ovarian cancer therapy.