Abstract 1136: Regulation of AMPK by androgen receptor signaling and its role in promoting prostate cancer through the use of autophagy

Abstract

Abstract While we now know that the androgen receptor (AR) is important for progression to the deadly advanced stages of prostate cancer, it is poorly understood what AR-regulated processes drive this pathology. Autophagy, an enigmatic cellular recycling process, has received increased attention as of late due to its potential oncogenic role in late-stage cancers. One of the master regulators of autophagy is the 5′-AMP-activated protein kinase (AMPK). Previous work from several independent laboratories has suggested AR signaling promotes cancer progression through an AMPK-dependent signaling mechanism. Further, it was demonstrated this enzymatic cascade was specifically regulated by Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2). Given AMPK's known role as a regulator of autophagy, we hypothesized that AR-mediated CaMKK2-AMPK signaling could promote prostate cancer through increasing cellular rates of autophagy. To test this hypothesis, we initially assessed whether AR signaling could regulate autophagy and if so, what effect(s) this had on prostate cancer cell growth and tumor formation. We then used a variety of pharmacological and molecular approaches to determine whether CaMKK2-AMPK signaling was required and sufficient to regulate autophagy and subsequent prostate cancer cell growth in vitro and in vivo. Here, we have determined that 1) AR regulates cell metabolism and cell growth in part by increasing autophagy in prostate cancer cells, 2) functional autophagy was clinically detected in metastatic, castration-resistant cancers but not treatment-naïve, localized tumors and 3) autophagy is required for prostate cancer progression in preclinical animal models. Additionally, AR-mediated autophagy was mediated through the direct expression of CaMKK2 and subsequent phosphorylation/activation of AMPK. Correspondingly, levels of both CaMKK2 and phosphorylated/activated AMPK correlated with prostate cancer progression in genetic mouse models and patients. Mechanistically, AR-mediated autophagy appears to promote cell growth by augmenting intracellular lipid accumulation, a hallmark of prostate cancers. Taken together, our findings converge to demonstrate that AR signaling can co-opt the AMPK signaling cascade, a known homeostatic mechanism, to promote prostate cancer by increasing autophagy. The current study points to the potential utility of developing metabolic-targeted therapies directed towards the CaMKK2-AMPK signaling axis for the treatment of prostate cancer. Further, an inhibitor of this signaling cascade could serve as an alternative, more specific therapeutic compared to existing inhibitors of autophagy that, to date, have demonstrated limited efficacy in clinical trials due to their toxicity and poor pharmacokinetics. Citation Format: Yan Shi, Efrosini Tsouko, Alicia M. Blessing, Jayantha Tennakoon, Jenny J. Han, Michael M. Ittmann, Daniel E. Frigo. Regulation of AMPK by androgen receptor signaling and its role in promoting prostate cancer through the use of autophagy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1136. doi:10.1158/1538-7445.AM2015-1136