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.
Highlights
Prostate cancer is responsible for nearly 30,000 deaths each year in the United States alone [1]
The findings of this study suggest that fatty acid metabolism plays a key role in coordinating endoplasmic reticulum (ER) and energetic homeostasis in prostate cancer cells, and that ER stress and AMPK activation caused by concurrent ATPcitrate lyase (ACLY) and androgen receptor (AR) inhibition leads to enhanced AR suppression, growth inhibition, and cell death
We report that inhibiting ACLY sensitizes castration-resistant prostate cancer (CRPC) cells to AR antagonism
Summary
Prostate cancer is responsible for nearly 30,000 deaths each year in the United States alone [1]. While localized prostate cancer has a favorable prognosis, some patients present with or develop metastatic disease. The androgen receptor (AR) plays a central role in prostate tumorigenesis at both early and late stages of the disease. Patients with metastatic prostate cancer typically respond well to androgen deprivation therapy. Tumors eventually develop resistance mechanisms that allow them to grow at castrate levels of androgen, resulting in a terminal disease known as castration-resistant prostate cancer (CRPC). In CRPC, AR activity frequently remains www.impactjournals.com/oncotarget crucial for disease progression, with tumors acquiring resistance mechanisms that enable AR transcriptional activity even with very low circulating levels of its canonical ligand [2,3,4,5,6,7]. Identification of more effective therapeutic approaches is urgently needed for CRPC patients
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