Prostate cancer is the most commonly diagnosed malignancy among men in industrialized countries, accounting for the second leading cause of cancer-related deaths. While we now know that the androgen receptor (AR) is important for progression to the deadly advanced stages of the disease, it is poorly understood what AR-regulated processes drive this pathology. Previous work from several independent laboratories has suggested AR signaling promotes prostate cancer through a Ca2+/calmodulin-dependent protein kinase kinase beta (CaMKK2)-dependent signaling mechanism. Further, it was demonstrated this enzymatic cascade promotes the use of sugars for cellular energy, a common trait for many cancers. Given CaMKK2's known role as a regulator of various aspects of metabolism, we hypothesized that CaMKK2 could promote prostate cancer cell growth through additional mechanisms beyond glycolysis.

To test our hypothesis, we used clinical samples to track the activation of downstream signaling components of CaMKK2 in prostate cancer. The mechanistic role of these components was then identified using a variety of cell-based assays and xenograft mouse models of prostate cancer.

Here, we demonstrate that AR-mediated CaMKK2 signaling regulates prostate cancer cell growth via the metabolic sensor 5′-AMP-activated protein kinase (AMPK), a kinase that classically regulates cellular energy homeostasis. In patients, activation of AMPK correlated with prostate cancer progression. Using a combination of radiolabeled assays and emerging metabolomic approaches, we also show that prostate cancer cells respond to androgen treatment by increasing not only rates of glycolysis, as is commonly seen in many cancers, but also glucose and fatty acid oxidation. Importantly, this effect was dependent on androgen-mediated AMPK activity. Our results further indicate that the AMPK-mediated metabolic changes increased intracellular ATP levels and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)-mediated mitochondrial biogenesis, affording distinct growth advantages to the prostate cancer cells. Correspondingly, we used outlier analysis to determine that PGC-1α is overexpressed in a subpopulation of clinical cancer samples. This was in contrast to what was observed in immortalized benign human prostate cells and a testosterone-induced rat model of benign prostatic hyperplasia.

Taken together, our findings converge to demonstrate that androgens can co-opt the CaMKK2-AMPK-PGC-1α signaling cascade, a known homeostatic mechanism, to increase prostate cancer cell growth. The current study points to the potential utility of developing metabolic-targeted therapies directed towards the CaMKK2-AMPK-PGC-1α signaling axis for the treatment of prostate cancer.

Citation Format: Daniel E. Frigo, Yan Shi, Jenny J. Han, Efrosini Tsouko, Michael M. Ittmann. CaMKK2-AMPK signaling facilitates androgen-mediated prostate cancer cell metabolism. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2450. doi:10.1158/1538-7445.AM2014-2450