Polyunsaturated fatty acids affect the localization and signaling of PIP3/AKT in prostate cancer cells. Carcinogenesis 2013 Sep;34(9):1968-75
Date
05/02/2013Pubmed ID
23633519Pubmed Central ID
PMC3765042DOI
10.1093/carcin/bgt147Scopus ID
2-s2.0-84878745139 (requires institutional sign-in at Scopus site) 54 CitationsAbstract
AKT is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates (PIPs) with phosphate groups at positions 3,4 and 3,4,5 on the inositol ring. In spite of extensive research on AKT, one aspect has been largely overlooked, namely the role of the fatty acid chains on PIPs. PIPs are phospholipids composed of a glycerol backbone with fatty acids at the sn-1 and sn-2 position and inositol at the sn-3 position. Here, we show that polyunsaturated fatty acids (PUFAs) modify phospholipid content. Docosahexaenoic acid (DHA), an ω3 PUFA, can replace the fatty acid at the sn-2 position of the glycerol backbone, thereby changing the species of phospholipids. DHA also inhibits AKT(T308) but not AKT(S473) phosphorylation, alters PI(3,4,5)P3 (PIP3) and phospho-AKT(S473) protein localization, decreases pPDPK1(S241)-AKT and AKT-BAD interaction and suppresses prostate tumor growth. Our study highlights a potential novel mechanism of cancer inhibition by ω3 PUFA through alteration of PIP3 and AKT localization and affecting the AKT signaling pathway.
Author List
Gu Z, Wu J, Wang S, Suburu J, Chen H, Thomas MJ, Shi L, Edwards IJ, Berquin IM, Chen YQAuthor
Michael J. Thomas PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsApoptosis
Cell Line, Tumor
Cell Proliferation
Fatty Acids, Omega-3
Fatty Acids, Unsaturated
Humans
Male
Mice
Mice, Transgenic
PTEN Phosphohydrolase
Phosphatidylinositol 3-Kinases
Prostatic Neoplasms
Proto-Oncogene Proteins c-akt
Signal Transduction
