Endothelin-1 inhibits apoptosis in prostate cancer.
Endothelin-1 (ET-1), produced by the prostate epithelia, likely plays an important role in the progression of prostate cancer. ET-1 can bind two receptor subtypes; generally, binding of the endothelin receptor A (ET(A)) induces a survival pathway, whereas binding of the endothelin receptor B (ET(B)) mediates clearance of circulating ET-1 as well as promotes apoptosis. In prostate carcinoma, hypermethylation of the ET(B) promoter results in repression of ET(B) expression, thereby eliminating the negative growth response that ET-1 binding elicits through this receptor. Therefore, activation of ET(A) exclusively provides a pathway for survival advantage. Our current studies examine the mechanisms by which activation of the ET(A) may allow growth/survival. ET-1 treatment of prostate tumor cells significantly decreased paclitaxel-induced apoptosis through activation of the ET(A) subtype. The anti-apoptotic effects of ET-1 are mediated, at least in part, through the Bcl-2 family. Although no significant changes in Bcl-2 expression occurred with ET-1 treatment, the pro-apoptotic family members Bad, Bax, and Bak all decreased significantly. Further analysis of the survival pathway demonstrated that phosphorylation of Akt occurs with ET-1 treatment in a time- and dose-dependent manner through phosphatidyinositol 3-kinase activation. These data support the combination of ET(A) antagonists and apoptosis-inducing therapies for prostate cancer treatment.
Nelson
Joel B
JB
Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232, USA.
Udan
Michael S
MS
Guruli
Georgi
G
Pflug
Beth R
BR
D017304:Annexin A5 / Q000494:pharmacology; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D019175:DNA Methylation; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000378:metabolism* / Q000502:physiology*; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017466:Receptors, Endothelin / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein
D017304:Annexin A5; C494819:BAD protein, human; C494772:BAK1 protein, human; C494826:BAX protein, human; D002352:Carrier Proteins; D019332:Endothelin-1; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017466:Receptors, Endothelin; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D019869:Phosphatidylinositol 3-Kinases; D017239:Paclitaxel