title: Targeting ACLY sensitizes castration-resistant prostate cancer cells to AR antagonism by impinging on an ACLY-AMPK-AR feedback mechanism.
abstract: The androgen receptor (AR) plays a central role in prostate tumor growth. Inappropriate reactivation of the AR after androgen deprivation therapy promotes development of incurable castration-resistant prostate cancer (CRPC). In this study, we provide evidence that metabolic features of prostate cancer cells can be exploited to sensitize CRPC cells to AR antagonism. We identify a feedback loop between ATP-citrate lyase (ACLY)-dependent fatty acid synthesis, AMPK, and the AR in prostate cancer cells that could contribute to therapeutic resistance by maintaining AR levels. When combined with an AR antagonist, ACLY inhibition in CRPC cells promotes energetic stress and AMPK activation, resulting in further suppression of AR levels and target gene expression, inhibition of proliferation, and apoptosis. Supplying exogenous fatty acids can restore energetic homeostasis; however, this rescue does not occur through increased β-oxidation to support mitochondrial ATP production. Instead, concurrent inhibition of ACLY and AR may drive excess ATP consumption as cells attempt to cope with endoplasmic reticulum (ER) stress, which is prevented by fatty acid supplementation. Thus, fatty acid metabolism plays a key role in coordinating ER and energetic homeostasis in CRPC cells, thereby sustaining AR action and promoting proliferation. Consistent with a role for fatty acid metabolism in sustaining AR levels in prostate cancer in vivo, AR mRNA levels in human prostate tumors correlate positively with expression of ACLY and other fatty acid synthesis genes. The ACLY-AMPK-AR network can be exploited to sensitize CRPC cells to AR antagonism, suggesting novel therapeutic opportunities for prostate cancer.
authors.affiliation: Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Supriya
authors.initials: S
authors.lastname: Shah
authors.affiliation: Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Whitney J
authors.initials: WJ
authors.lastname: Carriveau
authors.affiliation: Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Jinyang
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Sydney L
authors.initials: SL
authors.lastname: Campbell
authors.affiliation: Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.|Howard Hughes Medical Institute, Philadelphia, PA 19104, USA.
authors.forename: Piotr K
authors.initials: PK
authors.lastname: Kopinski
authors.affiliation: Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Hee-Woong
authors.initials: HW
authors.lastname: Lim
authors.affiliation: Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Natalie
authors.initials: N
authors.lastname: Daurio
authors.affiliation: Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Sophie
authors.initials: S
authors.lastname: Trefely
authors.affiliation: Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Kyoung-Jae
authors.initials: KJ
authors.lastname: Won
authors.affiliation: Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Wallace
authors.affiliation: Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Constantinos
authors.initials: C
authors.lastname: Koumenis
authors.affiliation: Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.|Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Mancuso
authors.affiliation: Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Wellen
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D001275:ATP Citrate (pro-S)-Lyase / Q000378:metabolism*; D059002:Androgen Receptor Antagonists / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D025461:Feedback, Physiological; D006801:Humans; D008297:Male; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism* / Q000473:pathology; D011494:Protein Kinases / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*
chemical_list: C410798:AR protein, human; D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011944:Receptors, Androgen; D001275:ATP Citrate (pro-S)-Lyase; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases
keywords: AMPK; ER stress; acetyl-CoA; fatty acid metabolism; prostate cancer