title: Androgens regulate prostate cancer cell growth via an AMPK-PGC-1α-mediated metabolic switch.
abstract: Prostate cancer is the most commonly diagnosed malignancy among men in industrialized countries, accounting for the second leading cause of cancer-related deaths. Although we now know that the androgen receptor (AR) is important for progression to the deadly advanced stages of the disease, it is poorly understood what AR-regulated processes drive this pathology. Here we demonstrate that AR regulates prostate cancer cell growth via the metabolic sensor 5'-AMP-activated protein kinase (AMPK), a kinase that classically regulates cellular energy homeostasis. In patients, activation of AMPK correlated with prostate cancer progression. Using a combination of radiolabeled assays and emerging metabolomic approaches, we also show that prostate cancer cells respond to androgen treatment by increasing not only rates of glycolysis, as is commonly seen in many cancers, but also glucose and fatty acid oxidation. Importantly, this effect was dependent on androgen-mediated AMPK activity. Our results further indicate that the AMPK-mediated metabolic changes increased intracellular ATP levels and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)-mediated mitochondrial biogenesis, affording distinct growth advantages to the prostate cancer cells. Correspondingly, we used outlier analysis to determine that PGC-1α is overexpressed in a subpopulation of clinical cancer samples. This was in contrast to what was observed in immortalized benign human prostate cells and a testosterone-induced rat model of benign prostatic hyperplasia. Taken together, our findings converge to demonstrate that androgens can co-opt the AMPK-PGC-1α signaling cascade, a known homeostatic mechanism, to increase prostate cancer cell growth. The current study points to the potential utility of developing metabolic-targeted therapies directed toward the AMPK-PGC-1α signaling axis for the treatment of prostate cancer.
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Tennakoon
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Han
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
authors.forename: E
authors.initials: E
authors.lastname: Tsouko
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: White
authors.affiliation: College of Optometry, University of Houston, Houston, TX, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Burns
authors.affiliation: Center for Genomic Medicine, Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: A
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Center for Genomic Medicine, Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: X
authors.initials: X
authors.lastname: Xia
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
authors.forename: O R
authors.initials: OR
authors.lastname: Ilkayeva
authors.affiliation: 1] Departments of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA [2] Departments of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA [3] Dan L. Duncan Cancer Center, Houston, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Xin
authors.affiliation: 1] Departments of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA [2] Dan L. Duncan Cancer Center, Houston, TX, USA [3] Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Ittmann
authors.affiliation: 1] Veterans Affairs Medical Center and South Florida VA Foundation for Research and Education, Miami, FL, USA [2] Department of Urology, Florida International University, Herbert Wertheim College of Medicine, Miami, FL, USA.
authors.forename: F G
authors.initials: FG
authors.lastname: Rick
authors.affiliation: 1] Veterans Affairs Medical Center and South Florida VA Foundation for Research and Education, Miami, FL, USA [2] Department of Pathology, University of Miami, Miller School of Medicine, Miami, FL, USA [3] Divisions of Hematology/Oncology, University of Miami, Miller School of Medicine, Miami, FL, USA [4] Division of Endocrinology, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA.
authors.forename: A V
authors.initials: AV
authors.lastname: Schally
authors.affiliation: 1] Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA [2] Center for Genomic Medicine, Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Frigo
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D018345:Mice, Knockout; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D010085:Oxidative Phosphorylation / Q000187:drug effects; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D017208:Rats, Wistar; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000728:Androgens; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011944:Receptors, Androgen; D014157:Transcription Factors; D015741:Metribolone; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human