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[Cancer Research 60, 3031-3038, June 1, 2000]
© 2000 American Association for Cancer Research

Molecular Biology and Genetics

Mitogenic Conversion of Transforming Growth Factor-ß1 Effect by Oncogenic Ha-Ras-induced Activation of the Mitogen-activated Protein Kinase Signaling Pathway in Human Prostate Cancer1

Bum-Joon Park, Jae-Il Park, Do-Sun Byun, Jae-Hoon Park and Sung-Gil Chi2

Department of Pathology, College of Medicine, Kyung Hee University, 130-701 Seoul, Republic of Korea

Elevated expression of transforming growth factor (TGF)-ß 1 has been implicated in prostate tumorigenesis despite its growth-inhibitory effect on normal epithelial and carcinoma cells of the prostate. In this study, we identified that G1-to-S transition of the cell cycle is stimulated by TGF-ß1 in the prostate cancer cell line TSU-Pr1. No mutation of signal mediators, including Smads, and induction of PAI-1 transcription indicated that the TGF-ß1 signaling cascade is functionally intact in this cell line. Whereas pharmacological inhibitors of various mitogenic signaling pathways showed no effects, blockade of the mitogen-activated protein kinase (MAPK) pathway by the MAPK kinase 1 inhibitor PD98059 restored the growth inhibitory role of TGF-ß1 in TSU-Pr1, which carries an oncogenic mutation in Ha-Ras (V12). Moreover, expression of antisense Ha-Ras or dominant negative Raf-1 abrogated the mitogenic effect of TGF-ß1 in TSU-Pr1, and the TGF-ß1 inhibition of DU145 was switched to stimulation by V12Ha-Ras transfection. Whereas the negative growth regulation by TGF-ß1 was completely inhibited by dominant negative Smad2, Smad3, or Smad4, its mitogenic effect was not affected, suggesting that this action is Smad-independent. Interestingly, whereas the TGF-ß1-mediated up-regulation of p15INK4B and p21WAF1 transcription was abolished in TSU-Pr1 and V12Ha-Ras-transfected DU145, inhibition of the Ras/MAPK pathway restored the TGF-ß1 induction of these genes. Taken together, our data suggest that prostate carcinomas with the Ras/MAPK pathway activation might have a selective growth advantage by autocrine TGF-ß1 production.




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