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The role of PI 3‐kinase p110β in AKT signally, cell survival, and proliferation in human prostate cancer cells
Author(s) -
Hill Karen M.,
Kalifa Sara,
Das Jharna R.,
Bhatti Tahira,
Gay Martha,
Williams Danielle,
TaliferroSmith LaTonia,
De Marzo Angelo M.
Publication year - 2010
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.21108
Subject(s) - lncap , du145 , protein kinase b , gene knockdown , biology , p110α , cancer research , cell growth , pi3k/akt/mtor pathway , kinase , prostate cancer , phosphoinositide 3 kinase , cell cycle , phosphorylation , microbiology and biotechnology , signal transduction , apoptosis , cancer , biochemistry , genetics
Abstract BACKGROUND Class IA PI 3‐kinases produce phosphatidylinositol (3,4,5)‐trisphosphate (PIP3). PIP3 is bound by AKT which facilities its activation by PDK1. Activated AKT promotes cell survival and stimulates cell proliferation. Class IA PI 3‐kinases are heterodimers consisting of a regulatory subunit p85 and a catalytic subunit p110. The p110α isoform has been shown to be mutated in a number of tumor types. A number of recent studies suggest that the p110β isoform may be functionally relevant in prostate cancer. In this study we extend this work to include the examination of the expression and functional properties of p110α and p110β in three different prostate cancer cell lines, DU145, LNCaP, PC3, as well as the non‐tumorigenic but immortalized RWPE1 prostate epithelial cell line. METHODS Western blot analysis was used to measure protein expression and quantitative real‐time PCR was used to measure mRNA levels. After targeted knockdown using isoform‐specific siRNAs to reduce PI 3‐kinase p110α or p110β isoform expression, we measured downstream signally events such as phosphorylation of AKT, ERK 1/2, PDK, and FOXO, as well as biological consequences such as changes in apoptosis, and alterations in cell cycle progression. RESULTS In all three prostate cancer cell lines examined, targeted knockdown of p110β, and not p110α, resulted in significantly reduced AKT, PDK, and FOXO phosphorylation. While knockdown of either p110 isoform resulted in an increase in apoptosis and a cell cycle arrest in G1 in the remaining non‐apoptotic cells, these effects were much more pronounced with knockdown of p110β. CONCLUSIONS Our results support the concept that p110β appears to be the predominant functional class I PI 3‐kinase isoform in prostate cancer cells. Prostate 70: 755–764, 2010. © 2010 Wiley‐Liss, Inc.