Targeting MCT4 to reduce lactic acid secretion and glycolysis for treatment of neuroendocrine prostate cancer. (14th June 2018)

• Record Type: Journal Article
• Authors: Choi, Stephen Yiu Chuen; Ettinger, Susan L.; Lin, Dong; Xue, Hui; Ci, Xinpei; Nabavi, Noushin; Bell, Robert H.; Mo, Fan; Gout, Peter W.; Fleshner, Neil E.; Gleave, Martin E.; Collins, Colin C.; Wang, Yuzhuo
• Is Part Of: Cancer medicine. Volume 7:Number 7(2018:Jul.)
• Page Start: 3385
• Page End: 3392
• Publication Date: 2018-06-14
• Subjects: cancer‐generated lactic acid -- MCT4 -- neuroendocrine prostate cancer -- patient‐derived xenografts -- reprogrammed cancer metabolism; 616.994005
• DOI: 10.1002/cam4.1587
• Languages: English
• ISSNs: 2045-7634

Abstract

Abstract: 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. Abstract : Neuroendocrine prostate cancer (NEPC) is considered a next‐generation clinical problem in prostate cancer management in urgent need of effective therapeutic strategies. This is the first description of NEPC metabolism in a clinically relevant and biologically functional manner, filling in a crucial knowledge gap regarding the metabolic phenotype of NEPC and its therapeutic possibilities.