The addition of human recombinant IFN-gamma (10(2) and 10(3) IU/ml) inhibited human prostatic JCA-1 cell growth by 27% and 64%, respectively. Since the high dose of IFN-gamma elicited an increase in G(1) concomitant with a decrease in G(2)/M phases of the cell cycle, changes in the expression of cell cycle regulatory protein molecules were analyzed by Western blots. Results of these experiments show that IFN-gamma down regulated the G(1)/S transition molecules, e.g., cyclin D1, the cyclin-dependent protein kinase Cdk4, and the retinoblastoma gene product (pRB), but increased the G(2)/M transition molecules, e.g., cyclin B1 and p34(cdc2) (Cdk1). Possible modulation of Cdk-inhibitors (CDKIs), e.g., p53 and p21(WAF1), which have checkpoint functions in the cell cycle, by IFN-gamma, was also studied. The p53 was induced by both 10(2) and 10(3) IU/ml IFN-gamma. At 10(3) IU/ml, IFN-gamma inhibited p21(WAF1), increased the expression of STAT1 alpha, and sustained the elevated STAT1 alpha for up to 96 h. Thus several mechanisms may be involved in the antiproliferative effects of IFN-gamma.

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