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CD46 is one of the complement-regulatory proteins expressed on the surface of normal and tumor cells for protection against complement-dependent cytotoxicity. Cancer cells need to access the blood circulation for continued growth and metastasis, thus exposing themselves to destruction by complement system components. Previous studies have established that the Stat3 transcription factor is persistently activated in a variety of human cancer cells and primary tumor tissues as compared to their normal counterparts. Persistent Stat3 activation in tumor cells has been shown to promote tumor cell proliferation, survival and evasion of cellular immunity. Using micorarray gene expression profiling, we identified the CD46 gene as a target for activated Stat3 in human breast and prostate cancer cells. The CD46 promoter contains two binding sites for activated Stat3 and deletions introduced into the consensus Stat3-binding sequences completely abolished Stat3 DNA-binding activity. CD46 promoter activity is induced by activation of Stat3 and blocked by a dominant-negative form of Stat3 in luciferase reporter assays. Furthermore, we show that inhibition of Stat3-mediated CD46 cell surface expression using Stat3 antisense oligonucleotides sensitizes DU145 prostate cancer cells to cytotoxicity in a complement lysis assay using rabbit anti-DU145 antiserum and rabbit complement. These results demonstrate that the CD46 promoter is induced by activated Stat3 and may protect human cancer cells from complement-mediated cytotoxicity, thereby facilitating growth and spread of tumor cells. Our finding that tumor Stat3 activity promotes CD46 expression provides direct evidence for a molecular mechanism whereby oncogenic signaling contributes to tumor cell evasion of antibody-mediated immunity.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]