Inhibition of CAMKK2 impairs autophagy and castration-resistant prostate cancer via suppression of AMPK-ULK1 signaling

Abstract

Previous work has suggested androgen receptor (AR) signaling mediates prostate cancer progression in part through the modulation of autophagy. However, clinical trials testing autophagy inhibition using chloroquine derivatives in men with castration-resistant prostate cancer (CRPC) have yet to yield promising results, potentially due to the side effects of this class of compounds. We hypothesized that identification of the upstream activators of autophagy in prostate cancer could highlight alternative, context-dependent targets for blocking this important cellular process during disease progression. Here, we used molecular, genetic and pharmacological approaches to elucidate an AR-mediated autophagy cascade involving Ca 2+ /calmodulin-dependent protein kinase kinase 2 (CAMKK2; a kinase with a restricted expression profile), 5’-AMP-activated protein kinase (AMPK) and Unc-51 like autophagy activating kinase 1 (ULK1), but independent of canonical mechanistic target of rapamycin (mTOR) activity. Increased CAMKK2-AMPK-ULK1 signaling correlated with disease progression in genetic mouse models and patient tumor samples. Importantly, CAMKK2 disruption impaired tumor growth and prolonged survival in multiple CRPC preclinical mouse models. Similarly, an inhibitor of AMPK-ULK1 blocked autophagy, cell growth and colony formation in prostate cancer cells. Collectively, our findings converge to demonstrate that AR can co-opt the CAMKK2-AMPK-ULK1 signaling cascade to promote prostate cancer by increasing autophagy. Thus, this pathway may represent an alternative autophagic target in CRPC.

Systemic ablation of Camkk2 impairs metastatic colonization and improves insulin sensitivity in TRAMP mice: Evidence for cancer cell-extrinsic CAMKK2 functions in prostate cancer

“…Also consistent with what we observed in TRAMP metastatic lesions, tumors grown in mice lacking Camkk2 exhibited decreased mTOR activity as assessed by p-S6 IHC (Figures 6D-E). Together, our data suggest that, in addition to the previously described cancer cell-intrinsic role of CAMKK2 in prostate cancer [3-5,29,30], CAMKK2 also promotes prostate cancer progression via tumor extrinsic mechanisms. Specifically, we propose that CAMKK2 enables metabolic syndrome, which causes increased levels of circulating insulin or some insulin-like molecule that can promote oncogenic mTOR signaling in distant prostate cancer cells (Figure 7).…”

“…Also consistent with what we observed in TRAMP metastatic lesions, tumors grown in mice lacking Camkk2 exhibited decreased mTOR activity as assessed by p-S6 IHC (Figures 6D-E). Together, our data suggest that, in addition to the previously described cancer cell-intrinsic role of CAMKK2 in prostate cancer [3][4][5]29,30],…”

“…To date, CAMKK2’s oncogenic effects in prostate cancer have solely been attributed to its known cancer cell-autonomous functions [3-5,29,30,33]. Given the multiple effects of Camkk2 ablation on cancer and macrometabolism, perhaps not surprisingly, here we observed for the first time an additional cancer cell-extrinsic role for CAMKK2 in prostate cancer progression (Figure 6).…”

Targeting autophagy in prostate cancer: preclinical and clinical evidence for therapeutic response

“…Autophagy inhibition after CAMKK2 knockdown occurs due to AMPK-ULK1 downregulation. [ 110 ] In vivo PC3 cells Enhancement ER stress induction via sphingosine-1-phosphate by enhancing ROS levels, autophagy induction and subsequent increase in prostate cancer survival. [ 111 ] In vivo HEK293T cells Reduction EP300/p300-CREBBP/CBP stimulates autophagy in prostate cancer cells, providing autophagic degradation of CTNNB1/β-catenin, and a significant decrease in progression and survival of prostate cancer cells.…”

Stromal Fibroblasts Counteract the Caveolin-1-Dependent Radiation Response of LNCaP Prostate Carcinoma Cells

“…At the same time, a decrease in cellular cholesterol was observed, which fits to the metabolic alterations, namely the increases in glycolysis to fulfill the respective energy demands, presumably caused by the reduced lipids and cholesterol utilization within CAV1 P132L LNCaP cells. The increasing energy demands for a fostered PCa cell growth further turned out to be based on a serine-threonine kinase AMP-activated protein kinase (AMPK)-mediated metabolic switch resulting in increased glycolysis rates together with an increase in glucose and fatty acid oxidation (61). Indeed, in patients, activation of AMPK correlated with PCa progression, further suggesting that AMPK might support PCa cells to survive under adverse nutritional conditions (62).…”