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

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)2490-2502
Number of pages13
JournalCancer Research
Volume78
Issue number10
DOIs
Publication statusPublished - May 15 2018

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Calcium-Calmodulin-Dependent Protein Kinases
Acetyl Coenzyme A
Organelles
Cell Movement
Prostatic Neoplasms
Cell Survival
Neoplasm Metastasis
Carcinogenesis
Carnitine O-Acetyltransferase
Clustered Regularly Interspaced Short Palindromic Repeats
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Metabolic Networks and Pathways
Anura
Oocytes
Prostate
Animal Models
Lymph Nodes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Organelle-derived acetyl-CoA promotes prostate cancer cell survival, migration, and metastasis via activation of calmodulin Kinase II. / Yu, Guoyu; Cheng, Chien Jui; Lin, Song Chang; Lee, Yu Chen; Frigo, Daniel E.; Yu-Lee, Li Yuan; Gallick, Gary E.; Titus, Mark A.; Nutt, Leta K.; Lin, Sue Hwa.

In: Cancer Research, Vol. 78, No. 10, 15.05.2018, p. 2490-2502.

Research output: Contribution to journalArticle

Yu, Guoyu ; Cheng, Chien Jui ; Lin, Song Chang ; Lee, Yu Chen ; Frigo, Daniel E. ; Yu-Lee, Li Yuan ; Gallick, Gary E. ; Titus, Mark A. ; Nutt, Leta K. ; Lin, Sue Hwa. / Organelle-derived acetyl-CoA promotes prostate cancer cell survival, migration, and metastasis via activation of calmodulin Kinase II. In: Cancer Research. 2018 ; Vol. 78, No. 10. pp. 2490-2502.
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AU - Lin, Song Chang

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AU - Frigo, Daniel E.

AU - Yu-Lee, Li Yuan

AU - Gallick, Gary E.

AU - Titus, Mark A.

AU - Nutt, Leta K.

AU - Lin, Sue Hwa

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AB - 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.

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