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

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 signalling prevents cell cycle progression while coordinating salvage efforts, chiefly enhancing glutamine assimilation into the TCA, to regain metabolic homeostasis. We confirm that MPC function is operant in PCa tumours 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 tumour growth in hormone-responsive and castrate-resistant conditions. Collectively, our findings characterize the MPC as a tractable therapeutic target in AR-driven prostate tumours.

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Fig. 1: The MPC is increased in PCa specimens and associated with poor clinical outcomes.
Fig. 2: AR controls the MPC in PCa through transcriptional regulation of MPC2.
Fig. 3: MPC inhibition delays proliferation and disrupts TCA outputs in AR-driven PCa models.
Fig. 4: MPC inhibition disrupts TCA function and prevents cell cycle progression.
Fig. 5: ISR signalling coordinates glutamine uptake and incorporation during MPC suppression.
Fig. 6: MPC inhibition suppresses tumour growth in preclinical models of AR-driven Pca.

Data availability

Analyzed RPPA data are available in Supplementary Data 2, analyzed RNA-sequencing data are available in Supplementary Data 3 and raw RNA-sequencing data are available under accession number GSE114708 on the National Center for Biotechnology Information Gene Expression Omnibus database. All other data described, analyzed and represented in the figures present in this study are available from the corresponding authors upon reasonable request.

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Acknowledgements

This study was supported by grants from the US National Institutes of Health (NIH): grant no. R21CA205257 (S.E.M.), F30CA196108 (D.A.B.), K01DK096093, R03DK105006, R01DK114356 (S.M.H.), R01CA211150 (J.A.B.), R01CA220297 (N.P.), F30AG050412 (H.M.-S.), U01CA167234 (A.S.), PO1DK113954 and HD08818 (B.W.O.), the Prostate Cancer Foundation (S.E.M.), The Caroline Weiss Law Scholar Foundation (S.E.M.), The MD Anderson Physician Scientist Development Program (S.E.M.), and the Cancer Research and Prevention Institute of Texas (RP140021-P5 (J.A.B.) and RP140106 (MDACC)). D.A.B. is a C. Thomas Caskey Scholar. D.A.B., H.M.-S. and M.P.H. are supported by the Baylor College of Medicine (BCM) Medical Scientist Training Program. S.M.H. is supported by the BCM Bridge to Independence Program and the Alkek Center for Molecular Discovery. M.P.H. is supported by the B.R.A.S.S. program, and the Robert and Janice McNair Foundation. V.P., N.P., A.S., K.R. and C.C. are supported by the CPRIT Core Facility Support Award RP120092, the NCI Cancer Center Support Grant P30CA125123, intramural funds from the Dan L. Duncan Cancer Center, and Alkek Center for Molecular Discovery. Additional support is from the American Cancer Society (127430-RSG-15-105-01-CNE to N.P.), CPRIT (RP150451 to A.S.) and GE Healthcare (J.A.B and C.W). The BCM Metabolomics Core is a designated Agilent Technologies Center for Excellence in Mass Spectrometry. We thank the following BCM Cores: Human Tissue Acquisition and Pathology (NCI-CA125123), Mouse Metabolism (director P. Saha), Integrated Microscopy (NCI-CA125123, NIDDK-56338-13/15, CPRIT RP150578, and the John S. Dunn Gulf Coast Consortium for Chemical Genomics), Cytometry and Cell Sorting (director J. Sederstrom, NIAID P30AI036211, NCI P30CA125123, and NCRR S10RR024574). We thank the M.D.A.C.C. Characterized Cell Line Core and Small Animal Imaging Facility (P30-CA016672). We thank J. Colca and the Metabolic Solutions Development Company for generously providing MSDC0160. We thank D. Townley for TEM imaging and B. Krishnan, M. Finegold, and G. Stoica for reviewing TEM images. We thank J. Rutter, D. Moore and A. Means for insightful conversations related to this manuscript. We acknowledge the joint participation by the Diana Helis Henry Medical Research Foundation through its direct engagement in the continuous active conduct of medical research (S.E.M. and A.S.).

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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 tumour growth experiments. P.K.S. performed U13C 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 dataset analysis. R.C. performed RNA sequencing. K.R. and C.C. assisted with RPPA data analysis, RNA sequencing data analysis, and AR ChIP sequencing 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.

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Correspondence to David A. Bader or Sean E. McGuire.

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Supplementary Text and Figures

Supplementary Figures 1–7

Reporting Summary

Supplementary Data 1

Informatic nomination and candidate genes

Supplementary Data 2

Reverse phase protein array (RPPA) data from ABL cells treated with UK5099

Supplementary Data 3

Analyzed RNA-sequencing data from ABL cells treated with UK5099

Supplementary Data 4

Reagent-related materials including antibodies, primers, sgRNA sequences, STR authentication data, and mycoplasma screening data

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Bader, D.A., Hartig, S.M., Putluri, V. et al. Mitochondrial pyruvate import is a metabolic vulnerability in androgen receptor-driven prostate cancer. Nat Metab 1, 70–85 (2019). https://doi.org/10.1038/s42255-018-0002-y

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Keywords

  • Mitochondrial Pyruvate Carrier (MPC)
  • Integrated Stress Response (ISR)
  • On Oxidative Phosphorylation (OXPHOS)
  • Reverse Phase Protein Array (RPPA)
  • The Cancer Genome Atlas (TCGA)

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