Targeting MCT4 to reduce lactic acid secretion and glycolysis for treatment of neuroendocrine prostate cancer,Cancer Medicine

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Targeting MCT4 to reduce lactic acid secretion and glycolysis for treatment of neuroendocrine prostate cancer
Cancer Medicine ( IF 2.9 ) Pub Date : 2018-06-14 , DOI: 10.1002/cam4.1587
Stephen Yiu Chuen Choi _{1,

2,

3} , Susan L Ettinger _{1,

2} , Dong Lin _{1,

2,

3} , Hui Xue ₃ , Xinpei Ci _{1,

2,

3} , Noushin Nabavi _{1,

2,

3} , Robert H Bell _{1,

2} , Fan Mo _{1,

2} , Peter W Gout ₃ , Neil E Fleshner ₄ , Martin E Gleave _{1,

2} , Colin C Collins _{1,

2} , Yuzhuo Wang _{1,

2,

3}

Affiliation

Development of neuroendocrine prostate cancer (NEPC) is emerging as a major problem in clinical management of advanced prostate cancer (PCa). As increasingly potent androgen receptor (AR)‐targeting antiandrogens are more widely used, PCa transdifferentiation into AR‐independent NEPC as a mechanism of treatment resistance becomes more common and precarious, since NEPC is a lethal PCa subtype urgently requiring effective therapy. Reprogrammed glucose metabolism of cancers, that is elevated aerobic glycolysis involving increased lactic acid production/secretion, plays a key role in multiple cancer‐promoting processes and has been implicated in therapeutics development. Here, we examined NEPC glucose metabolism using our unique panel of patient‐derived xenograft PCa models and patient tumors. By calculating metabolic pathway scores using gene expression data, we found that elevated glycolysis coupled to increased lactic acid production/secretion is an important metabolic feature of NEPC. Specific inhibition of expression of MCT4 (a plasma membrane lactic acid transporter) by antisense oligonucleotides led to reduced lactic acid secretion as well as reduced glucose metabolism and NEPC cell proliferation. Taken together, our results indicate that elevated glycolysis coupled to excessive MCT4‐mediated lactic acid secretion is clinically relevant and functionally important to NEPC. Inhibition of MCT4 expression appears to be a promising therapeutic strategy for NEPC.

中文翻译：

靶向 MCT4 减少乳酸分泌和糖酵解治疗神经内分泌前列腺癌

神经内分泌前列腺癌 (NEPC) 的发展正在成为晚期前列腺癌 (PCa) 临床管理中的一个主要问题。随着靶向雄激素受体 (AR) 的抗雄激素药物的应用越来越广泛，PCa 转分化为不依赖 AR 的 NEPC 作为一种治疗耐药机制变得更加普遍和不稳定，因为 NEPC 是一种致命的 PCa 亚型，迫切需要有效的治疗。重新编程的癌症葡萄糖代谢，即涉及增加乳酸产生/分泌的有氧糖酵解升高，在多种癌症促进过程中起着关键作用，并与治疗学发展有关。在这里，我们使用我们独特的患者来源的异种移植 PCa 模型和患者肿瘤组检查了 NEPC 葡萄糖代谢。通过使用基因表达数据计算代谢途径评分，我们发现升高的糖酵解与增加的乳酸产生/分泌相结合是 NEPC 的一个重要代谢特征。反义寡核苷酸对 MCT4（质膜乳酸转运蛋白）表达的特异性抑制导致乳酸分泌减少以及葡萄糖代谢减少和 NEPC 细胞增殖。综上所述，我们的结果表明，升高的糖酵解与过度的 MCT4 介导的乳酸分泌相结合，对 NEPC 具有临床相关性和功能重要性。抑制 MCT4 表达似乎是一种很有前途的 NEPC 治疗策略。反义寡核苷酸对 MCT4（质膜乳酸转运蛋白）表达的特异性抑制导致乳酸分泌减少以及葡萄糖代谢减少和 NEPC 细胞增殖。综上所述，我们的结果表明，升高的糖酵解与过度的 MCT4 介导的乳酸分泌相结合，对 NEPC 具有临床相关性和功能重要性。抑制 MCT4 表达似乎是一种很有前途的 NEPC 治疗策略。反义寡核苷酸对 MCT4（质膜乳酸转运蛋白）表达的特异性抑制导致乳酸分泌减少以及葡萄糖代谢减少和 NEPC 细胞增殖。综上所述，我们的结果表明，升高的糖酵解与过度的 MCT4 介导的乳酸分泌相结合，对 NEPC 具有临床相关性和功能重要性。抑制 MCT4 表达似乎是一种很有前途的 NEPC 治疗策略。

更新日期：2018-06-15

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