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Mark A White Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, Texas, USA
Department of Biology and Biochemistry, University of Houston, Houston, Texas, USA

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Efrosini Tsouko Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, Texas, USA
Department of Biology and Biochemistry, University of Houston, Houston, Texas, USA

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Chenchu Lin Department of Cancer Systems Imaging, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas, USA

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Kimal Rajapakshe Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA

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Jeffrey M Spencer Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, Texas, USA
Department of Biology and Biochemistry, University of Houston, Houston, Texas, USA

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Sandi R Wilkenfeld Department of Cancer Systems Imaging, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas, USA

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Sheiva S Vakili Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, Texas, USA
Department of Biology and Biochemistry, University of Houston, Houston, Texas, USA

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Thomas L Pulliam Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, Texas, USA
Department of Biology and Biochemistry, University of Houston, Houston, Texas, USA
Department of Cancer Systems Imaging, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

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Dominik Awad Department of Cancer Systems Imaging, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas, USA

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Fotis Nikolos Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA

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Rajasekhara Reddy Katreddy Department of Biology and Biochemistry, University of Houston, Houston, Texas, USA

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Benny Abraham Kaipparettu Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA

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Arun Sreekumar Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA

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Xiaoliu Zhang Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, Texas, USA
Department of Biology and Biochemistry, University of Houston, Houston, Texas, USA

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Edwin Cheung Biology and Pharmacology, Genome Institute of Singapore, A*STAR, Singapore, Singapore
Faculty of Health Sciences, University of Macau, Taipa, Macau, China

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Cristian Coarfa Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA

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Daniel E Frigo Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, Texas, USA
Department of Biology and Biochemistry, University of Houston, Houston, Texas, USA
Department of Cancer Systems Imaging, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
Molecular Medicine Program, The Houston Methodist Research Institute, Houston, Texas, USA

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Despite altered metabolism being an accepted hallmark of cancer, it is still not completely understood which signaling pathways regulate these processes. Given the central role of androgen receptor (AR) signaling in prostate cancer, we hypothesized that AR could promote prostate cancer cell growth in part through increasing glucose uptake via the expression of distinct glucose transporters. Here, we determined that AR directly increased the expression of SLC2A12, the gene that encodes the glucose transporter GLUT12. In support of these findings, gene signatures of AR activity correlated with SLC2A12 expression in multiple clinical cohorts. Functionally, GLUT12 was required for maximal androgen-mediated glucose uptake and cell growth in LNCaP and VCaP cells. Knockdown of GLUT12 also decreased the growth of C4-2, 22Rv1 and AR-negative PC-3 cells. This latter observation corresponded with a significant reduction in glucose uptake, indicating that additional signaling mechanisms could augment GLUT12 function in an AR-independent manner. Interestingly, GLUT12 trafficking to the plasma membrane was modulated by calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2)-5′-AMP-activated protein kinase (AMPK) signaling, a pathway we previously demonstrated to be a downstream effector of AR. Inhibition of CaMKK2-AMPK signaling decreased GLUT12 translocation to the plasma membrane by inhibiting the phosphorylation of TBC1D4, a known regulator of glucose transport. Further, AR increased TBC1D4 expression. Correspondingly, expression of TBC1D4 correlated with AR activity in prostate cancer patient samples. Taken together, these data demonstrate that prostate cancer cells can increase the functional levels of GLUT12 through multiple mechanisms to promote glucose uptake and subsequent cell growth.

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Neha Venkatesh Baylor College of Medicine, Houston, TX, USA

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Rebecca S Tidwell Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Yao Yu Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Ana Aparicio Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Amado J Zurita Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Sumit K Subudhi Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Bilal A Siddiqui Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Sagar S Mukhida Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Justin R Gregg Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Paul G Corn Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Efstratios Koutroumpakis Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Jennifer L McQuade Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Daniel E Frigo Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Patrick G Pilie Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Chad Huff Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Christopher J Logothetis Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Andrew W Hahn Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Hormone therapy (HT) to treat prostate cancer is reported to cause adverse changes in body composition. Clinically, interpatient body composition changes are heterogeneous, but the biological and clinical determinants of body composition toxicity are unknown. Herein, we test the hypothesis that inherited polymorphisms in steroidogenic genes are associated with differential changes in body composition after HT. Men with biochemically recurrent prostate cancer (BCR) who received 8 months of LHRH analog (LHRHa) +/− abiraterone acetate (AAP) were eligible if they had: i) CT imaging of L3 prior to and after treatment; and ii) nucleated cells collected. Cardiometabolic co-morbidities were retrospectively extracted. Body composition was measured using an AI-based segmentation tool. Germline DNA whole exome or genome sequencing was performed. In 162 men treated with 8 months of HT, median skeletal muscle mass (SMMi) loss was 6.6% and subcutaneous adipose gain was 12.3%. Men with type 2 diabetes had higher losses of SMMi after treatment (−11.1% vs −6.3%, P = 0.003). For the 150 men with germline NGS, SRD5A2 rs523349 genotype was associated with differential loss in skeletal muscle density after HT, (−1.3% vs −7.1%, P = 0.04). In addition, the HSD3B1 rs104703 genotype was associated with decreased baseline visceral adipose tissue (63.0 cm2/m2 vs 77.9, P = 0.05). In men with BCR, HT induced notable loss of skeletal muscle and increased subcutaneous adipose tissue. An inherited polymorphism in SRD5A2 and T2DM was associated with differential skeletal muscle toxicity. These findings suggest that inherited polymorphisms may contribute to the body composition toxicity observed with HT.

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