The MCT4 Gene: A Novel, Potential Target for Therapy of Advanced Prostate Cancer
The MCT4 Gene: A Novel, Potential Target for Therapy of Advanced Prostate Cancer
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DOI：
10.1158/1078-0432.ccr-15-1624
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发表时间：
2016-06-01
影响因子：
11.5
通讯作者：
Wang, Yuzhuo
中科院分区：
文献类型：
--
作者：
Choi, Stephen Yiu Chuen;Xue, Hui;Wang, Yuzhuo
目的：去势抵抗性前列腺癌（CRPC）的治疗是临床上的一个重大挑战。雄激素受体信号导向策略在CRPC治疗中不具有治愈性，需要针对替代性关键癌症特性的新策略。利用重新编程的葡萄糖代谢（有氧糖酵解），癌细胞通常会分泌过量的乳酸到其微环境中，促进癌症的发展，生存和进展。细胞乳酸分泌被认为主要是由MCT 4介导的，MCT 4是一种质膜转运蛋白。因此，MCT 4基因为癌症提供了一个独特的、潜在的治疗靶点。实验设计：对各种Gleason分级的人前列腺癌的组织微阵列进行MCT 4蛋白染色。设计特异性的靶向MCT 4反义寡核苷酸（MCT 4阿索），并检查候选MCT 4 ASO对（i）MCT 4表达、乳酸分泌/含量、葡萄糖消耗、糖酵解基因表达和人CRPC细胞增殖以及（ii）裸鼠中PC-3肿瘤生长的影响。用候选MCT 4 ASO处理PC-3、DU 145和C4-2 CRPC培养物导致MCT 4表达、乳酸分泌显著抑制，细胞内乳酸水平升高，有氧糖酵解和细胞增殖显著降低。治疗PC-3荷瘤裸鼠的MCT 4 ASOs显着抑制肿瘤生长，而不诱导主要的宿主toxicity.Conclusions：MCT 4靶向ASOs，抑制乳酸分泌可能是有用的CRPC和其他癌症的治疗，因为它们可以干扰重新编程的能量代谢的癌症，一个新兴的标志癌症。（C）2016年AACR。
Purpose: The management of castration-resistant prostate cancer (CRPC) is a major challenge in the clinic. Androgen receptor signaling-directed strategies are not curative in CRPC therapy, and new strategies targeting alternative, key cancer properties are needed. Using reprogrammed glucose metabolism (aerobic glycolysis), cancer cells typically secrete excessive amounts of lactic acid into their microenvironment, promoting cancer development, survival, and progression. Cellular lactic acid secretion is thought to be predominantly mediated by MCT4, a plasma membrane transporter protein. As such, the MCT4 gene provides a unique, potential therapeutic target for cancer.Experimental Design: A tissue microarray of various Gleason grade human prostate cancers was stained for MCT4 protein. Specific, MCT4-targeting antisense oligonucleotides (MCT4 ASO) were designed and candidate MCT4 ASOs checked for effects on (i) MCT4 expression, lactic acid secretion/content, glucose consumption, glycolytic gene expression, and proliferation of human CRPC cells and (ii) growth of PC-3 tumors in nude mice.Results: Elevated MCT4 expression was associated with human CRPC and an earlier time to relapse. The treatment of PC-3, DU145, and C4-2 CRPC cultures with candidate MCT4 ASOs led to marked inhibition of MCT4 expression, lactic acid secretion, to increased intracellular lactic acid levels, and markedly reduced aerobic glycolysis and cell proliferation. Treatment of PC-3 tumor-bearing nude mice with the MCT4 ASOs markedly inhibited tumor growth without inducing major host toxicity.Conclusions: MCT4-targeting ASOs that inhibit lactic acid secretion may be useful for therapy of CRPC and other cancers, as they can interfere with reprogrammed energy metabolism of cancers, an emerging hallmark of cancer. (C)2016 AACR.