Organelle-derived acetyl-CoA promotes prostate cancer cell survival, migration, and metastasis via activation of calmodulin kinase II

Although emerging evidence suggests a potential role of calcium/calmodulin-dependent kinase II (CaMKII) in prostate cancer (PCa), its role in PCa tumorigenesis is largely unknown. Here we examine whether the acetyl CoA-CaMKII pathway, first described in frog oocytes, promotes PCa tumorigenesis. In human PCa specimens, metastatic PCa expressed higher levels of active CaMKII compared to localized PCa. Correspondingly, basal CaMKII activity was significantly higher in the more tumorigenic PC3 and PC3-mm2 cells relative to the less tumorigenic LNCaP and C4-2B4 cells. Deletion of CaMKII by CRISPR/Cas9 in PC3-mm2 cells abrogated cell survival under low-serum conditions, anchorage-independent growth and cell migration; overexpression of constitutively active CaMKII in C4-2B4 cells promoted these phenotypes. In an animal model of PCa metastasis, genetic ablation of CaMKII reduced PC3-mm2 cell metastasis from the prostate to the lymph nodes. Knockdown of the acetyl-CoA transporter carnitine acetyltransferase (CRAT) abolished CaMKII activation, providing evidence that acetyl-CoA generated from organelles is a major activator of CaMKII. Genetic deletion of the β-oxidation rate-limiting enzyme ACOX family proteins decreased CaMKII activation, while overexpression of ACOXI increased CaMKII activation. Overall, our studies identify active CaMKII as a novel connection between organelle β-oxidation and acetyl-CoA transport with cell survival, migration, and PCa metastasis.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2tJIGrb