Multiple myeloma exhibits novel dependence on GLUT4, GLUT8, and GLUT11: implications for glucose transporter-directed therapy
Multiple myeloma exhibits novel dependence on GLUT4, GLUT8, and GLUT11: implications for glucose transporter-directed therapy
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DOI：
10.1182/blood-2011-09-377846
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发表时间：
2012-05-17
期刊：
影响因子：
20.3
通讯作者：
Shanmugam, Mala
中科院分区：
文献类型：
--
作者：
McBrayer, Samuel K.;Cheng, Javelin C.;Shanmugam, Mala
多发性骨髓瘤是以葡萄糖消耗增加为特征的众多恶性肿瘤之一，这种现象在这种疾病中具有重要的预后意义。很少有研究集中在阐明癌症中葡萄糖转运蛋白（GLUT）激活的分子基础上，这些知识可以促进识别有前途的治疗靶点。为了解决这个问题，我们进行了基因表达谱研究，涉及骨髓瘤细胞系和原代细胞以及正常淋巴细胞，以揭示骨髓瘤中GLUT家族成员的失调。我们的数据表明，骨髓瘤细胞表现出依赖于组成型细胞表面定位的GLUT 4的基础葡萄糖消耗，Mcl-1的表达，生长和生存的维护。我们还确定了神秘的转运蛋白GLUT 8和GLUT 11的活性是骨髓瘤增殖和生存力所必需的，尽管其功能可能与全细胞葡萄糖供应不同。作为GLUT靶向化合物治疗潜力的原理证明，我们纳入了FDA批准的HIV蛋白酶抑制剂利托那韦（ritonavir）对细胞系和原代细胞产生抗骨髓瘤作用的证据，利托那韦对GLUT 4产生选择性脱靶抑制作用。我们的工作揭示了新型GLUT家族成员的关键作用，并强调了一种治疗策略，该策略需要选择性GLUT抑制，以特异性靶向癌症中的异常葡萄糖代谢。（血。2012; 119（20）：4686-4697）
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 underpinnings of glucose transporter (GLUT) activation in cancer, knowledge that could facilitate identification of promising therapeutic targets. To address this issue, we performed gene expression profiling studies involving myeloma cell lines and primary cells as well as normal lymphocytes to uncover deregulated GLUT family members 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 proliferation and viability in myeloma, albeit because of functionalities probably distinct from whole-cell glucose supply. As proof of principle regarding the therapeutic potential of GLUT-targeted compounds, 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 inhibitory effect on GLUT4. Our work reveals critical roles for novel GLUT family members and highlights a therapeutic strategy entailing selective GLUT inhibition to specifically target aberrant glucose metabolism in cancer. (Blood. 2012; 119(20): 4686-4697)