Activated signal transducers and activators of transcription 3 signaling induces CD46 expression and protects human cancer cells from complement-dependent cytotoxicity.
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 signal transducers and activators of transcription 3 (STAT3) transcription factor is persistently activated in a wide variety of human cancer cells and primary tumor tissues compared with their normal counterparts. Using microarray gene expression profiling, we identified the CD46 gene as a target for activated STAT3 signaling in human breast and prostate cancer cells. The CD46 promoter contains two binding sites for activated STAT3 and mutations introduced into the major site abolished STAT3 binding. Chromatin immunoprecipitation confirms binding of STAT3 to the CD46 promoter. CD46 promoter activity is induced by activation of STAT3 and blocked by a dominant-negative form of STAT3 in luciferase reporter assays. CD46 mRNA expression is induced by interleukin-6 and by transient transfection of normal human epithelial cells with a persistently active mutant construct of STAT3, STAT3C. Furthermore, we show that inhibition of STAT3-mediated CD46 cell surface expression sensitizes DU145 prostate cancer cells to cytotoxicity in an in vitro complement lysis assay using rabbit anti-DU145 antiserum and rabbit complement. These results show that activated STAT3 signaling induces the CD46 promoter and protects human cancer cells from complement-dependent cytotoxicity, suggesting a potential mechanism whereby oncogenic signaling contributes to tumor cell evasion of antibody-mediated immunity.
Buettner
Ralf
R
Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA. rbuettner@coh.org
Huang
Mei
M
Gritsko
Tanya
T
Karras
Jim
J
Enkemann
Steve
S
Mesa
Tania
T
Nam
Sangkil
S
Yu
Hua
H
Jove
Richard
R
D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D003165:Complement System Proteins / Q000494:pharmacology*; D024202:Electrophoretic Mobility Shift Assay; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005799:Genes, Dominant; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D015850:Interleukin-6 / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051916:Membrane Cofactor Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D046228:Microarray Analysis; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011817:Rabbits; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
D007074:Immunoglobulin G; D015850:Interleukin-6; D051916:Membrane Cofactor Protein; D050796:STAT3 Transcription Factor; D003165:Complement System Proteins; D008156:Luciferases