Targeting ACLY sensitizes castration-resistant prostate cancer cells to AR antagonism by impinging on an ACLY-AMPK-AR feedback mechanism
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Supriya Shah1, Whitney J. Carriveau1, Jinyang Li1, Sydney L. Campbell1, Piotr K. Kopinski5,6, Hee-Woong Lim2, Natalie Daurio3, Sophie Trefely1, Kyoung-Jae Won2, Douglas C. Wallace5, Constantinos Koumenis3, Anthony Mancuso1,4, Kathryn E. Wellen1
1Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
2Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
3Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
4Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
5Center for Mitochondrial and Epigenomic Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
6Howard Hughes Medical Institute, Philadelphia, PA 19104, USA
Kathryn E. Wellen, e-mail: email@example.com
Keywords: acetyl-CoA, prostate cancer, fatty acid metabolism, AMPK, ER stress
Received: December 22, 2015 Accepted: May 08, 2016 Published: May 27, 2016
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.
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