Insensitivity to growth inhibition by TCF-β1 correlates with a lack of inhibition of the CDK2 activity in prostate carcinoma cells

Abstract

TGF-β is a potent growth inhibitor of epithelial cells. However, many transformed cells have lost their sensitivity to this growth inhibitory effect. The molecular mechanism of such insensitivity is not yet understood. Here, we have studied the TGF-β1 effect on normal human prostate and carcinoma cells. Our results showed that normal cells were sensitive to growth inhibition, whereas tumor cells were not or only minimally inhibited regardless of the concentration of TGF-β1 (20 to 80 pM) or time of exposure (1-5 days). p21(WAF1/Cip1/Sdi1) and p15(INK4B) but not p27(KIP1) were detectable by Western blotting in normal and tumor cells. TGF-β1 treatment increased the association of p21(WAF1/Cip1/Sdi1) With the Cdk2/cyclin E complex in both normal and prostate tumor cells. However, there was no increase in the association of p15(INK4B) nor p27(Kip1) with the Cdk/cyclin complexes. In normal cells, the increase in the association of p21(WAF1/Cip1/Sdi1). With the Cdk2/cyclin E complex resulted in inhibition of the Cdk2 activity. In contrast, although there was an increase in the association of p21(WAF1/Cip1/Sdi1) with the Cdk2/cyclin E complex in tumor cells, there was no inhibition of the Cdk2 activity. These results indicate that a lack of inhibition of the Cdk2 activity correlates with insensitivity to TGF-β1 in prostate tumor cells.