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.

Reprogramming of fatty acid metabolism in cancer

“…For instance, in CRPC cells, inhibition of ACLY disrupts ER and energy homoeostasis in CRPC cells, leading to AMPK activation and sensitisation to androgen receptor inhibitors. 213 Intriguingly, supplementation of exogenous FAs is sufficient to restore hormone resistance in CRPC cells by alleviating the ER and energy stress instigated by ACLY inhibition, demonstrating the importance of an ACLY-AMPK network in regulating energy homoeostasis that could be exploited pharmacologically. 213 Indeed, several AMPK-activating therapies such as metformin have shown anticancer and anti-inflammatory properties, and importantly are well tolerated in patients.…”

Lipid pathway deregulation in advanced prostate cancer

“…A recent study has demonstrated that it is possible to target the ACLY-AMPK-AR axes to sensitise CRPC cells to AR antagonism (65). A combined pharmacological approach with an AR antagonist and 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.…”

ATP-Citrate Lyase Controls a Glucose-to-Acetate Metabolic Switch

“…Silencing or inhibition of ACLY suppresses the proliferation of many cancer cell lines and impairs tumor growth (Bauer et al, 2005; Hanai et al, 2012; Hatzivassiliou et al, 2005; Migita et al, 2008; Shah et al, 2016; Zaidi et al, 2012). Depending on context, ACLY silencing or inhibition can also promote senescence (Lee et al, 2015), induce differentiation (Hatzivassiliou et al, 2005), or suppress cancer stemness (Hanai et al, 2013), further pointing to its potential as a target for cancer therapy.…”