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Down-Regulation of neu/HER-2 by Interferon- in Prostate Cancer Cells¹

Department of Microbiology and Cell Science, University of Florida, Gainesville, Florida 32611

Interferons (IFNs) are known to possess potent antitumor properties. Previous studies have indicated that IFNs are capable of modulating the expression of various tumor suppressor genes and oncogenes. In this study, we looked at the effect of IFN- on the neu/HER-2 proto-oncogene in the DU145, LNCaP, and PC-3 prostate cancer cell lines. IFN- inhibited cell proliferation in both DU145 and PC-3 cells in a dose-dependent manner, whereas no inhibition of proliferation was seen in LNCaP cells. Correspondingly, IFN- treatment of DU145 and PC-3 cells resulted in an increased production of the cyclin-dependent kinase inhibitor p21^WAF1, whereas no increase in p21^WAF1 was seen in LNCaP cells. In addition, IFN- induced phosphorylation of signal transducer and activator of transcription (STAT) 1 in DU145 and PC-3 cells, but not in LNCaP cells. Consistent with these findings, we found that IFN- treatment of DU145 and PC-3 cells caused a reduction in neu/HER-2 expression, with no change seen in the LNCaP cell line. Transfection and overexpression of the transcriptional coactivator p300 in PC-3 cells suppressed the reduction in neu/HER-2 expression after IFN- treatment, suggesting a role for p300 in neu/HER-2 expression. The antiproliferative activity and p21^WAF1 production of these cells after IFN- treatment were found to be reduced as well. We propose that the down-regulation of neu/HER-2 by IFN- occurs via the interaction of phosphorylated STAT1 with p300 because IFN- activities requiring phosphorylated STAT1 are reduced in cells overexpressing p300. These findings suggest that neu/HER-2 may play a role in the growth of some prostate cancers and that IFN- may suppress such cancers by down-regulation of neu/HER-2.

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