Abstract 1268: Aberrant plasma membrane localization of GLUT4 sustains the glycolytic phenotype in multiple myeloma

The incurable plasma cell malignancy multiple myeloma (MM) is characterized by the progressive development of chemoresistance, thus warranting the design of new therapeutic strategies tailored to unique molecular mechanisms driving tumor propagation. One aspect of myeloma pathogenesis which has not been exploited therapeutically is an abnormal avidity for glucose. Inhibition of glucose metabolism has broad applicability in cancer and has demonstrated in vitro potency; unfortunately, previous attempts focusing on hexokinase inhibition have been largely unsuccessful. Targeting the upstream process of glucose transport has not been a major area of investigation due to the common association between GLUT1 and cancer and the importance of GLUT1 in many normal tissues. However, the specific glucose transporters responsible for maintaining the glycolytic phenotype in myeloma have not been identified, leaving open the possibility that family members other than GLUT1 play important roles in this cellular context. Therefore, we undertook an unbiased real time PCR-based screen of GLUT gene expression profiles in myeloma cell lines and control B lymphocytes. GLUTs 4, 8, and 11 exhibit widespread overexpression in MM cells with no significant difference noted in GLUT1 levels. Examination of microarray studies of MM patient samples and western blot analyses of MM cell lines and normal B cells confirm the upregulation of GLUT8 and GLUT11 in clinical specimens and at the protein level. However, we did not find further evidence for GLUT4 overexpression. After evaluating the subcellular localization of GLUT4 through microscopy, we determined that a substantial fraction of GLUT4 protein is constitutively mislocalized to the plasma membrane in myeloma cells, an event normally regulated by insulin in non-malignant tissues. Indeed, cell fractionation studies demonstrate a dramatic increase in plasma membrane GLUT4 content in MM cell lines relative to PBMC. Lentiviral transduction of GLUT4-targeted shRNA verifies the functional relevance of GLUT4 activity, as MM cells with reduced GLUT4 expression exhibit dramatic deficiencies in glucose transport and lactate production rates, which leads to growth inhibition and significant cell death. Similar studies with a GLUT1-targeted shRNA reveal comparable trends but less potent effects. Next, we investigated a class of HIV protease inhibitors which elicit off-target inhibitory effects on GLUT4 in vivo. Treatment with these compounds recapitulates the effects of GLUT4 knockdown, thus supporting the relevance of GLUT4 in myeloma. These studies represent the first time a prominent, functional role for GLUT4 has been demonstrated in any cancer and highlight a therapeutic strategy involving the repositioning of an FDA-approved class of drugs to target myeloma cell metabolism. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1268. doi:10.1158/1538-7445.AM2011-1268