LYMPHOID NEOPLASIA Multiple myeloma exhibits novel dependence on GLUT4, GLUT8, and GLUT11: implications for glucose transporter-directed therapy

Multiple myeloma is one of numerous malignancies characterized by increased glucose consumption, a phenomenon with significant prognostic implications in this disease. Few studies have focused on elucidating the molecular underpin-nings of glucose transporter (GLUT) acti-vation in cancer, knowledge that could facilitate identification of promising thera-peutic targets. To address this issue, we performed gene expression profiling stud-ies involving myeloma cell lines and pri-mary cells as well as normal lymphocytes to uncover deregulated GLUT family mem-bers in myeloma. Our data demonstrate that myeloma cells exhibit reliance on constitutively cell surface-localized GLUT4 for basal glucose consumption, maintenance of Mcl-1 expression, growth, and survival. We also establish that the activities of the enigmatic transporters GLUT8 and GLUT11 are required for prolif-eration and viability in myeloma, albeit because of functionalities probably dis-tinct from whole-cell glucose supply. As proof of principle regarding the therapeu-tic potential of GLUT-targeted com-pounds, we include evidence of the anti-myeloma effects elicited against both cell lines and primary cells by the FDA-approved HIV protease inhibitor ritonavir, which exerts a selective off-target inhibi-tory effect on GLUT4. Our work reveals critical roles for novel GLUT family mem-bers and highlights a therapeutic strategy entailing selective GLUT inhibition to spe-cifically target aberrant glucose metabo-lism in cancer. (Blood. 2012;119(20): 4686-4697