Mitogenic conversion of transforming growth factor-beta1 effect by oncogenic Ha-Ras-induced activation of the mitogen-activated protein kinase signaling pathway in human prostate cancer.
Elevated expression of transforming growth factor (TGF)-beta1 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-beta1 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-beta1 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-beta1 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-beta1 in TSU-Pr1, and the TGF-beta1 inhibition of DU145 was switched to stimulation by V12Ha-Ras transfection. Whereas the negative growth regulation by TGF-beta1 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-beta1-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-beta1 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-beta1 production.
Park
B J
BJ
Department of Pathology, College of Medicine, Kyung Hee University, Seoul, Republic of Korea.
Park
J I
JI
Byun
D S
DS
Park
J H
JH
Chi
S G
SG
D002453:Cell Cycle; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005434:Flow Cytometry; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D015689:Oncogene Protein p21(ras) / Q000378:metabolism*; D018807:Polymorphism, Single-Stranded Conformational; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D015689:Oncogene Protein p21(ras); C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one