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Impaired -Interferon Signaling in Transitional Cell Carcinoma

Lack of p48 Expression in 5637 Cells¹

Departments of Urology [S. F. M., R. R. R., P. C. S., M. S. K., A. C. N., S. K. B.] and Cancer Biology [R. R. R., P. C. S., S. K. B.], Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195

The limited success of IFN- therapy for clinical treatment of transitional cell carcinoma (TCC) has prompted us to investigate the responsiveness of TCC lines to IFN-. The response to IFN- in terms of 561 gene induction, an IFN-stimulated response element-containing IFN-/ß-inducible gene, and IFN-stimulated gene factor 3 (ISGF3) formation was normal in primary human urothelial cells. We tested the antiproliferative effects of IFN- in three TCC lines as a measure of IFN- responsiveness, and variable patterns of growth inhibition were observed in three TCC lines. More than 90% growth inhibition was noted in TCCSUP cells, whereas only 40% and 10% inhibition by IFN- was observed in 5637 and HT1197 cells, respectively. IFN- treatment formed extremely low levels of ISGF3 in electrophoretic mobility shift assays in these later two relatively insensitive cells. In addition, expression of the 561 gene was significantly reduced in these two TCC lines by Northern blots. We have further identified a low expression level of Tyk2 in HT1197 cells compared with two other TCCs. This suggests that an extremely low ISGF3 level after IFN- treatment may be due to low Tyk2 expression or other unidentified defects. In 5637 cells, p48 protein expression was undetectable. This undetectable p48 expression is not due to a deletion in the coding region because the correct size protein is detected following IFN- treatment. Consequently, the ISGF3 complex formation and 561 gene induction were restored by IFN- pretreatment plus IFN- treatment. Introduction of p48 expressing plasmid into 5637 cells was sufficient to form the ISGF3 complex by IFN- treatment, suggesting the defect lies in the expression of p48 protein in 5637 cells. Detailed mechanistic understanding of the action of IFNs in bladder cancer cell lines may explain the abrogated therapeutic response of IFN- in the clinical treatment of TCCs.

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