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      Mitochondrial pyruvate import is a metabolic vulnerability in androgen receptor-driven prostate cancer

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          Abstract

          Specific metabolic underpinnings of androgen receptor (AR)-driven growth in prostate adenocarcinoma (PCa) are largely undefined, hindering the development of strategies to leverage the metabolic dependencies of this disease when hormonal manipulations fail. Here we show that the mitochondrial pyruvate carrier (MPC), a critical metabolic conduit linking cytosolic and mitochondrial metabolism, is transcriptionally regulated by AR. Experimental MPC inhibition restricts proliferation and metabolic outputs of the citric acid cycle (TCA) including lipogenesis and oxidative phosphorylation in AR-driven PCa models. Mechanistically, metabolic disruption resulting from MPC inhibition activates the eIF2α/ATF4 integrated stress response (ISR). ISR signaling prevents cell cycle progression while coordinating salvage efforts, chiefly enhanced glutamine assimilation into the TCA, to regain metabolic homeostasis. We confirm that MPC function is operant in PCa tumors in-vivo using isotopomeric metabolic flux analysis. In turn, we apply a clinically viable small molecule targeting the MPC, MSDC0160, to pre-clinical PCa models and find that MPC inhibition suppresses tumor growth in hormone-responsive and castrate-resistant conditions. Collectively, our findings characterize the MPC as a tractable therapeutic target in AR-driven prostate tumors.

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          Most cited references50

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          The integrated stress response.

          In response to diverse stress stimuli, eukaryotic cells activate a common adaptive pathway, termed the integrated stress response (ISR), to restore cellular homeostasis. The core event in this pathway is the phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) by one of four members of the eIF2α kinase family, which leads to a decrease in global protein synthesis and the induction of selected genes, including the transcription factor ATF4, that together promote cellular recovery. The gene expression program activated by the ISR optimizes the cellular response to stress and is dependent on the cellular context, as well as on the nature and intensity of the stress stimuli. Although the ISR is primarily a pro-survival, homeostatic program, exposure to severe stress can drive signaling toward cell death. Here, we review current understanding of the ISR signaling and how it regulates cell fate under diverse types of stress.
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            Lactate Metabolism in Human Lung Tumors

            Cancer cells consume glucose and secrete lactate in culture. It is unknown whether lactate contributes to energy metabolism in living tumors. We previously reported that human non-small cell lung cancers (NSCLC) oxidize glucose in the tricarboxylic acid (TCA) cycle. Here we show that lactate is also a TCA cycle carbon source for NSCLC. In human NSCLC, evidence of lactate utilization was most apparent in tumors with high 18 fluorodeoxyglucose uptake and aggressive oncological behavior. Infusing human NSCLC patients with 13 C-lactate revealed extensive labeling of TCA cycle metabolites. In mice, deleting monocarboxylate transporter-1 (MCT1) from tumor cells eliminated lactate-dependent metabolite labeling, confirming tumor-cell autonomous lactate uptake. Strikingly, directly comparing lactate and glucose metabolism in vivo indicated that lactate's contribution to the TCA cycle predominates. The data indicate that tumors, including bona fide human NSCLC, can use lactate as a fuel in vivo. Human non-small cell lung cancer preferentially utilizes lactate over glucose to fuel TCA cycle and sustain tumor metabolism in vivo.
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              Divergent clonal evolution of castration resistant neuroendocrine prostate cancer

              An increasingly recognized resistance mechanism to androgen receptor (AR)-directed therapy in prostate cancer involves epithelial plasticity, wherein tumor cells demonstrate low to absent AR expression and often neuroendocrine features. The etiology and molecular basis for these “alternative” treatment-resistant cell states remain incompletely understood. Here, by analyzing whole exome sequencing data of metastatic biopsies from patients, we observed significant genomic overlap between castration resistant adenocarcinoma (CRPC-Adeno) and neuroendocrine histologies (CRPC-NE); analysis of serial progression samples points to a model most consistent with divergent clonal evolution. Genome-wide DNA methylation revealed marked epigenetic differences between CRPC-NE and CRPC-Adeno that also designated cases of CRPC-Adeno with clinical features of AR-independence as CRPC-NE, suggesting that epigenetic modifiers may play a role in the induction and/or maintenance of this treatment-resistant state. This study supports the emergence of an alternative, “AR-indifferent” cell state through divergent clonal evolution as a mechanism of treatment resistance in advanced prostate cancer.
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                Author and article information

                Journal
                101736592
                48119
                Nat Metab
                Nat Metab
                Nature metabolism
                2522-5812
                15 April 2019
                19 November 2018
                January 2019
                14 June 2019
                : 1
                : 1
                : 70-85
                Affiliations
                [1 ]Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
                [2 ]Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, Baylor College of Medicine, Houston, TX 77030, USA
                [3 ]Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
                [4 ]Department of Imaging Physics, Division of Diagnostic Imaging, The University of Texas M.D. Anderson Cancer Center, Houston TX 77030, USA
                [5 ]Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA
                [6 ]Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
                [7 ]Department of Medicine, Section of Hematology & Oncology, Baylor College of Medicine, Houston, TX 77030, USA
                [8 ]Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA
                [9 ]Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston TX 77030, USA
                Author notes

                Author Contributions

                D.A.B. and S.E.M. conceptualized the study. D.A.B., S.M.H., and S.E.M. designed experiments. D.A.B. wrote the manuscript with editorial input from all authors. D.A.B. performed all experiments with assistance as noted: S.M.H. assisted with immunofluorescence. A.S., V.P., and N.P. assisted with mass spectroscopy measurements. L.Z., C.F., E.A.S., and H.M.S. assisted with animal tumor growth experiments. P.K.S. performed U 13C glucose infusions. B.W.O. and A.P. provided reagents and performed in-vitro transcription experiments. J.A.B. and C.W. performed hyperpolarized pyruvate imaging. M.P.H., C.C., and K.R. assisted with clinical data set analysis. R.C. performed RNA-sequencing. K.R. and C.C. assisted with RPPA data analysis, RNA-Seq data analysis, and AR ChIP-Seq integrative analysis. M.M.I. provided clinical specimens. N.M. provided prostate cancer models. All work was performed under the supervision of S.E.M.

                [* ]Correspondence should be addressed to S.E.M. ( Sean.McGuire@ 123456bcm.edu ) or D.A.B. ( Bader@ 123456bcm.edu )
                Article
                NIHMS1508495
                10.1038/s42255-018-0002-y
                6563330
                31198906
                bfdf614d-7cd4-4c2b-8a84-9c45a9810bf5

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