The effect of dexamethasone on human mucin 1 expression and antibody-dependent complement sensitivity in a prostate cancer cell line in vitro and in vivo.
Dexamethasone has been shown to up-regulate human mucin 1 (MUC1) expression in certain types of cancer cell lines in vitro, suggesting that this gluocorticoid may enhance MUC1-based immunotherapies. Here we investigated the effect of dexamethasone on MUC1 expression in the DU145 human prostate cancer cell line in terms of antibody-mediated complement-dependent cell lysis. Cells treated with 1 x 10-8 m dexamethasone in vitro expressed maximal levels of MUC1 after 6 days, with an approximately 3-fold increase over MUC1 levels on untreated cells. DU145 cells were highly resistant to lysis by anti-MUC1 antibody and complement, and their susceptibility to antibody and complement was unaffected by dexamethasone treatment. However, dexamethasone also induced expression of the complement inhibitor decay accelerating factor (DAF) on DU145 cells. Blocking or overcoming the function of DAF resulted in enhanced complement-dependent lysis of dexamethasone-treated cells with anti-MUC1 antibodies, indicating that the failure of dexamethasone to enhance the complement susceptibility of DU145 cells was caused by the up-regulated expression of DAF. We also investigated MUC1 expression in vivo and found that MUC1 expression was significantly up-regulated on tumour cells isolated from immune-deficient mice that had been injected with dexamethasone. However, in contrast to in vitro data, there was no difference between the levels of DAF expressed on tumour-derived DU145 cells isolated from either phosphate buffered saline (PBS)-treated or dexamethasone-treated mice, and tumour cells isolated from dexamethasone-treated mice were more sensitive to complement-mediated lysis. In the broad context of immunotherapy, the in vivo data support the use of dexamethasone as an adjunct treatment. Up-regulated DAF expression would not be a favourable outcome of dexamethasone treatment in terms of complement-dependent antibody therapy, but the in vivo data caution against extrapolation of in vitro data with regard to the modulation of complement inhibitors reported here and elsewhere.
Imai
Masaki
M
Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA.
Hwang
Hee-Young
HY
Norris
James S
JS
Tomlinson
Stephen
S
D000818:Animals; D000906:Antibodies / Q000276:immunology; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D045744:Cell Line, Tumor; D051152:Clusterin; D003169:Complement Inactivator Proteins / Q000032:analysis; D003165:Complement System Proteins / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D003907:Dexamethasone / Q000494:pharmacology*; D005434:Flow Cytometry / Q000379:methods; D005938:Glucocorticoids / Q000494:pharmacology*; D006023:Glycoproteins / Q000276:immunology; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018832:Molecular Chaperones / Q000276:immunology; D009077:Mucins / Q000032:analysis*; D009363:Neoplasm Proteins / Q000276:immunology; D011471:Prostatic Neoplasms / Q000276:immunology*; D015854:Up-Regulation
D000906:Antibodies; D018931:Antineoplastic Agents, Hormonal; C495242:CLU protein, human; C495243:Clu protein, mouse; D051152:Clusterin; D003169:Complement Inactivator Proteins; D005938:Glucocorticoids; D006023:Glycoproteins; D018832:Molecular Chaperones; D009077:Mucins; D009363:Neoplasm Proteins; D003907:Dexamethasone; D003165:Complement System Proteins