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Tyrphostin AG825 Triggers p38 Mitogen-activated Protein Kinase-dependent Apoptosis in Androgen-independent Prostate Cancer Cells C4 and C4-2¹

Departments of Molecular Pharmacology and Experimental Therapeutics [H. M.], Urology Research [H. M., L. J. S., D. J. T.], and Biochemistry and Molecular Biology [D. J. T.], Mayo Clinic and Foundation, Rochester, Minnesota 55905

Prostate cancer (PCa) progression is aided by abnormal autocrine growth factor loops. We screened for small cell-permeable inhibitors of receptor tyrosine kinases that could block their signaling and trigger cell death in PCa cell lines. We found that the human epidermal growth factor receptor (HER)-2/neu inhibitor tyrphostin AG825 is preferentially toxic to PCa cells that are phenotypically androgen independent. These effects were dose and time dependent in the human LNCaP, C4, and C4-2 cell line models of progression and correlated with the inhibition of HER-2/neu phosphoactivation and its down-regulation. In addition, we show that the inhibition of HER-2/neu signaling with AG825 triggers an imbalance between extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase activation, which leads to p38-dependent apoptosis. Inhibition of HER-1 with Compound 56 had no effect. These findings suggest that the androgen-independent C4 and C4-2 cells can be killed by selectively inhibiting their HER-2/neu signaling pathway and provide insights into the mechanism of action of AG825 in PCa cells.

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