Androgens regulate prostate cancer cell growth via an AMPK-PGC-1α-mediated metabolic switch

Abstract

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. Here, we demonstrate that AR 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 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 AMPK-PGC-1α signaling axis for the treatment of prostate cancer.

Organ-Specific Cancer Metabolism and Its Potential for Therapy

“…Accordingly, prostate cancer is affected by 2-deoxyglucose [158][159][160]. This is further in agreement with cell line studies, which show that the metastastic androgen-sensitive cell line LNCaP and the castration-resistant low-differentiation cell lines DU-145 and PC-3 are sensitive to glucose starvation [152] and that androgen signaling enhances the expression of glycolytic enzymes [161][162][163]. However, whether or not an increased expression of the glucose transporter 1 or other hexose transporters are causal for this phenotype is still a matter of debate, since histological data are inconclusive [164][165][166][167].…”

“…Increased androgen receptor signaling might directly or with the aid of other signaling pathways increase overall metabolic activity [161,162,167]. Specifically, AMPK and consequently PGC-1α could be activated by androgen receptor-dependent CAMKK induction, which is connected to increased glycolysis and lactate excretion, but also mitochondrial biogenesis [161,163]. Increased glycolytic metabolism is further supported by higher hexokinase 2 expression, which is at least partly triggered by androgen-receptor-dependent activation of PKA/CREB [162].…”

The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation

“…This notion is compatible with the fact that AMPK activates catabolic processes and inhibits anabolic processes, an unfavorable context for cell proliferation (10). In contrast, several recent reports have also shown that gain of function of AMPK and PGC-1α is a driver of tumorigenesis via maintenance of metabolic homeostasis, promotion of metastasis, and support of cancer cell survival (41)(42)(43)(54)(55)(56)(57)(58). This concept is supported by the fact that loss of AMPK or its upstream activator LKB1 is associated with apoptosis under bioenergetically stressful conditions (54).…”

Preclinical efficacy of growth hormone-releasing hormone antagonists for androgen-dependent and castration-resistant human prostate cancer

“…The mainstay treatment for advanced or metastatic prostate carcinoma is androgen-deprivation therapy (ADT) (2,3). Although initially ADT is beneficial and reduces tumor burden, tumors ultimately recur in a form termed hormoneinsensitive or castration-resistant prostate cancer (CRPC) (4). There are few treatment options for CRPC, none of which is curative; thus, new approaches to treat or prevent CRPC or its progression are needed.…”