Lysophosphatidic acid promotes survival of androgen-insensitive prostate cancer PC3 cells via activation of NF-kappaB.
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.
Raj
Ganesh V
GV
Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.
Sekula
Jeffrey A
JA
Guo
Rishu
R
Madden
John F
JF
Daaka
Yehia
Y
D000230:Adenocarcinoma / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction
D008246:Lysophospholipids; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D011944:Receptors, Androgen; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C032881:lysophosphatidic acid