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

Guoyu Yu, Chien Jui Cheng, Song Chang Lin, Yu Chen Lee, Daniel E. Frigo, Li Yuan Yu-Lee, Gary E. Gallick, Mark A. Titus, Leta K. Nutt, Sue Hwa Lin

研究成果: 雜誌貢獻文章同行評審

23 引文 斯高帕斯(Scopus)


Although emerging evidence suggests a potential role of calcium/calmodulin-dependent kinase II (CaMKII) in prostate cancer, its role in prostate cancer tumorigenesis is largely unknown. Here, we examine whether the acetyl CoA-CaMKII pathway, first described in frog oocytes, promotes prostate cancer tumorigenesis. In human prostate cancer specimens, metastatic prostate cancer expressed higher levels of active CaMKII compared with localized prostate cancer. 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 prostate cancer 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 abolished CaMKII activation, providing evidence that acetyl-CoA generated from organelles is a major activator of CaMKII. Genetic deletion of the b-oxidation rate-limiting enzyme ACOX family proteins decreased CaMKII activation, whereas overexpression of ACOXI increased CaMKII activation. Overall, our studies identify active CaMKII as a novel connection between organelle b-oxidation and acetyl-CoA transport with cell survival, migration, and prostate cancer metastasis. Significance: This study identifies a cell metabolic pathway that promotes prostate cancer metastasis and suggests prostate cancer may be susceptible to b-oxidation inhibitors.
頁(從 - 到)2490-2502
期刊Cancer Research
出版狀態已發佈 - 5月 15 2018

ASJC Scopus subject areas

  • 腫瘤科
  • 癌症研究


深入研究「Organelle-derived acetyl-CoA promotes prostate cancer cell survival, migration, and metastasis via activation of calmodulin Kinase II」主題。共同形成了獨特的指紋。