GLUT1 is an AR target contributing to tumor growth and glycolysis in castration-resistant and enzalutamide-resistant prostate cancers
GLUT1 is an AR target contributing to tumor growth and glycolysis in castration-resistant and enzalutamide-resistant prostate cancers
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GLUT1 是一种 AR 靶点，有助于去势抵抗性和恩杂鲁胺抵抗性前列腺癌中的肿瘤生长和糖酵解
DOI：
10.1016/j.canlet.2020.05.007
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发表时间：
2020-08-10
期刊：
影响因子：
9.7
通讯作者：
Ye, Dingwei
中科院分区：
文献类型：
--
作者：
Wang, Jun;Xu, Wenhao;Ye, Dingwei
去势抵抗性前列腺癌（CRPC）的F-18-FDG PET SUVmax高于去势敏感性前列腺癌，这表明CRPC更需要葡萄糖代谢。靶向癌细胞中的葡萄糖代谢对于癌症治疗仍然具有吸引力。葡萄糖转运蛋白（glucose transporters，GLUTs）是葡萄糖代谢的第一步，也是葡萄糖代谢的限速步骤。在这里，我们研究了葡萄糖转运蛋白的关键介质，并评估其在CRPC临床前模型中的治疗价值。F-18-FDG PET显示CRPC的SUVmax高于对化疗敏感的前列腺癌，GLUT 1表达与SUVmax呈正相关，并与CRPC预后较差相关。在CRPC和Enzalutamide耐药前列腺癌的异种移植模型中，GLUT 1抑制显著抑制细胞生长、糖酵解和肿瘤体积。染色质免疫沉淀和双荧光素酶报告基因分析表明，雄激素受体（AR）直接与GLUT 1基因启动子结合，促进GLUT 1的转录。GLUT 1抑制和Enzalutamide联合使用可显著抑制CRPC细胞的增殖和糖酵解，并诱导细胞凋亡。我们的结果表明GLUT 1是AR靶点，并与恩杂鲁胺表现出协同作用。GLUT 1可能作为CRPC和Enzalutamide耐药前列腺癌的一个有前途的治疗靶点。
Castration-resistant prostate cancer (CRPC) displays a higher F-18-FDG PET SUVmax than hormone-sensitive prostate cancer, which suggests a greater need for glucose metabolism in CRPC. Targeting glucose metabolism in cancer cells remains attractive for cancer treatment. Glucose transporters (GLUTs) meditate the first and rate-limiting step of glucose metabolism. Here, we investigated the key mediator of glucose transporters and evaluated its therapeutic value in a preclinical model of CRPC. F-18-FDG PET showed a higher SUVmax in CRPC than in hormone-sensitive prostate cancer, and GLUT1 expression positively correlated with SUVmax and was associated with a worse CRPC outcome. GLUT1 inhibition significantly suppressed cell growth, glycolysis and tumor volume in a xenograft model both in CRPC and enzalutamide-resistant prostate cancer. Chromatin immunoprecipitation and dual luciferase reporter assay showed that androgen receptor (AR) directly bound to the GLUT1 gene promoter to promote GLUT1 transcription. Combining GLUT1 inhibition and enzalutamide remarkably suppressed proliferation and glycolysis and induced apoptosis in CRPC cells. Our results suggest that GLUT1 is an AR target and displays synergistic effects with enzalutamide. GLUT1 may act as a promising therapeutic target in CRPC and enzalutamide-resistant prostate cancer.