Lysophosphatidic acid promotes survival of androgen-insensitive prostate cancer PC3 cells via activation of NF-kappaB.

Journal Article

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-kappaB (NF-kappaB) was determined biochemically by nuclear translocation and transcriptional activation. Human tissue was analyzed for nuclear expression of NF-kappaB by immunohistochemistry. RESULTS: Molecular dissection of the LPA-regulated PC3 cell survival revealed the sequential phosphorylation of Akt, IkappaB, and transcriptional activation of NF-kappaB. Both Akt and NF-kappaB 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-kappaB is constitutively activated in prostate cancers, but not in benign prostate tissues. CONCLUSIONS: Targeted disruption of the LPA receptor-Akt-NF-kappaB signaling axis may be effective for the treatment of androgen-insensitive prostate cancer.

Full Text

Duke Authors

Cited Authors

  • Raj, GV; Sekula, JA; Guo, R; Madden, JF; Daaka, Y

Published Date

  • October 1, 2004

Published In

Volume / Issue

  • 61 / 2

Start / End Page

  • 105 - 113

PubMed ID

  • 15305333

International Standard Serial Number (ISSN)

  • 0270-4137

Digital Object Identifier (DOI)

  • 10.1002/pros.20083

Language

  • eng

Conference Location

  • United States