Endothelin-1 inhibits apoptosis in prostate cancer

Joel B Nelson, Michael S Udan, Georgi Guruli, Beth R Pflug
Neoplasia: An International Journal for Oncology Research 2005, 7 (7): 631-7
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.

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