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Lysophosphatidic acid promotes survival of androgen‐insensitive prostate cancer PC3 cells via activation of NF‐κB
Author(s) -
Raj Ganesh V.,
Sekula Jeffrey A.,
Guo Rishu,
Madden John F.,
Daaka Yehia
Publication year - 2004
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.20083
Subject(s) - prostate cancer , lysophosphatidic acid , cancer research , protein kinase b , androgen receptor , prostate , biology , lncap , tissue microarray , medicine , endocrinology , cancer , signal transduction , receptor , microbiology and biotechnology
BACKGROUND Dysregulated cell survival contributes to the poor efficacy of many chemotherapeutic regimens for patients with advanced prostate cancer. In this study we examined ability of the lipid growth factor lysophosphatidic acid (LPA), a G protein‐coupled receptor (GPCR) ligand, to promote prostate cell survival. METHODS PC3 cells were used as a model to study mechanisms involved in survival of androgen‐insensitive prostate cancer cells. Cell survival was measured by FACS analysis of cell cycle parameters after propidium iodide or annexin V and 7‐AAD immunostaining. Activation state of nuclear facor‐κB (NF‐κB) was determined biochemically by nuclear translocation and transcriptional activation. Human tissue was analyzed for nuclear expression of NF‐κB by immunohistochemistry. RESULTS Molecular dissection of the LPA‐regulated PC3 cell survival revealed the sequential phosphorylation of Akt, IκB, and transcriptional activation of NF‐κB. Both Akt and NF‐κB were required to escape serum deprivation‐induced cell death since their inhibition abrogated the LPA‐mediated PC3 cell survival. Data from archival human tissue show that NF‐κB is constitutively activated in prostate cancers, but not in benign prostate tissues. CONCLUSIONS Targeted disruption of the LPA receptor‐Akt–NF‐κB signaling axis may be effective for the treatment of androgen‐insensitive prostate cancer. © 2004 Wiley‐Liss, Inc.