Abstract
The recent progresses in understanding of cancer glycolytic phenotype have offered new strategies to manage ovarian cancer and other malignancies. However, therapeutic targeting of glycolysis to treat cancer remains unsuccessful due to complex mechanisms of tumor glycolysis and the lack of selective, potent and safe glycolytic inhibitors. Recently, BAY-876 was identified as a new-generation inhibitor of glucose transporter 1 (GLUT1), a GLUT isoform commonly overexpressed but functionally poorly defined in ovarian cancer. Notably, BAY-876 has not been evaluated in any cell or preclinical animal models since its discovery. We herein took advantage of BAY-876 and molecular approaches to study GLUT1 regulation, targetability, and functional relevance to cancer glycolysis. The anti-tumor activity of BAY-876 was evaluated with ovarian cancer cell line- and patient-derived xenograft (PDX) models. Our results show that inhibition of GLUT1 is sufficient to block basal and stress-regulated glycolysis, and anchorage-dependent and independent growth of ovarian cancer cells. BAY-876 dramatically inhibits tumorigenicity of both cell line-derived xenografts and PDXs. These studies provide direct evidence that GLUT1 is causally linked to the glycolytic phenotype in ovarian cancer. BAY-876 is a potent blocker of GLUT1 activity, glycolytic metabolism and ovarian cancer growth, holding promise as a novel glycolysis-targeted anti-cancer agent.
Highlights
Ovarian cancer is the most lethal of gynecological malignancies
Our results provide the first direct evidence that glucose transporter 1 (GLUT1) is indispensable for both basal and induced glycolysis in ovarian cancer cells
In the presence of BAY-876, the glycolytic induction was dramatically blunted (Figure 2B). These results indicate that GLUT1 acts as a critical mediator of both basal and stress-induced glycolysis in ovarian cancer cells
Summary
Ovarian cancer is the most lethal of gynecological malignancies. The dismal prognosis results from the inability to detect the disease at an early, curable stage and the lack of effective therapies for recurrent disease which inevitably develops chemotherapy resistance [1]. In ovarian cancer, there is little direct evidence for a causal role of GLUT1 in the development or maintenance of tumor glycolytic phenotype [24,25]. Among small-molecule GLUT1 inhibitors [23,26,27,28,29,30,31,32], STF-31 [23] and WZB117 [26] were reported to inhibit GLUT1-mediated glucose uptake at low μM concentrations and to show some anti-cancer activities in xenograft tumor models. We validate GLUT1 as an effective anti-cancer target by demonstrating that BAY-876 blocks GLUT1-dependent glycolytic metabolism in ovarian cancer, resulting in potent inhibition of tumor cell growth in vitro and in vivo
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