AMPK direct activation inhibits prostate cancer growth through lipogenesis blockade: clinical implications for patients with concomitant metabolic syndrome

G. ZADRA; C. PHOTOPOULOS; P. HEIDARI; T. GERKE; H. LIU; N. SCAGLIA; N. MARTIN; ET AL.

Congreso; Keystone Symposia, Cancer and Metabolism; 2012

Deregulation of the lipogenic and the mTORC1 pathways is a common feature of primary and advanced Prostate Cancer (PCa). Since the energy sensor AMPK links cell metabolism to growth by the negative regulation of these anabolic pathways, it represents an ideal therapeutic target. The current AMPK activators AICAR and metformin, although effective, show many non-specific effects; thus the role of AMPK activation in PCa therapy still remains elusive. To address this issue, we characterized MT 63-78, a novel and specific direct activator of AMPK. We demonstrated that AMPK activation per se inhibits PCa cell growth in vitro and in xenograft models in LKB1-independent manner. Most importantly, we provided evidence that blockade of de novo lipogenesis is the main mechanism of PCa growth inhibition by the compound. On this basis, we analyzed the feasibility of measuring tumor uptake of 11C-acetate to monitor in vivo efficacy of AMPK direct activators. Finally, we generated an mRNA signature associated with fatty acid synthase overexpression as indicative of a lipogenic phenotype. We analyzed 64 tumors from PCa patients evaluated for features of metabolic syndrome, commonly characterized by dysfunctional AMPK. Gene set enrichment analysis showed significant enrichment of this signature, suggesting these patients as candidate group for treatment with AMPK direct activators. This work was supported by the Prostate Cancer Foundation and by the NIH grant RO1CA131945 to M.L.