Abstract 722: Reciprocal regulation of MUC4 and HER-2 by the corticosteroid fluticasone propionate in pancreatic cancer cells: Potential role in anticancer therapy

Abstract

Abstract Pancreatic cancer (PC) has a dismal five-year survival rate of about 5%. MUC4 mucin is a large glycoprotein aberrantly expressed by PC cells. We have previously shown that MUC4 stabilizes the receptor tyrosine kinase HER-2. Fluticasone propionate (FP) is a potent glucocorticoid used in the treatment of asthma. It has previously been reported to repress the expression of MUC4 in cultured nasal polyp cells. However, its role in regulating MUC4 expression and PC cell behavior has not been examined. In the present study, we hypothesized that FP represses MUC4 expression in PC cells and thus could be useful in the treatment of PC. An in silico analysis of the MUC4 promoter revealed several glucocorticoid response elements (GREs) upstream of the transcription start site. Further, an analysis of glucocorticoid receptor α isoform (GRα) and MUC4 expression status revealed that PC cells express varying levels of the two genes. Based on MUC4 and GRα status, we chose four PC cell lines- Capan-1 (MUC4+,GRhigh), HPAF/CD18 (MUC4+,GRlow), ASPC-1 (MUC4-,GRhigh) and MiaPaca (MUC4-,GRlow) and examined the effect of FP treatment on MUC4 expression, intracellular signaling and cellular function. We also examined the effects of FP on the growth of subcutaneously implanted Capan-1 cells in SCID mice. FP repressed MUC4 expression in both the MUC4+ cells in a dose and time dependent manner. However, while a nearly 90% reduction of MUC4 was observed in Capan-1 cells within 24 hr, a <50% reduction was observed in HPAF/CD18 cells even after 5 days of treatment with FP (100nM). Of significance, treatment of GRhigh (but not GRlow) cells was also associated with an increase in the expression of HER-2 and E-cadherin, and downregulation of N-cadherin, cyclin A and p44/p42 MAPK, while the expression of p53, NFκB and total ERK remained unaltered. FP pre-treatment increased the sensitivity of GRhigh cells to Docetaxel and 5FU (in a MUC4 independent manner). FP also significantly reduced the growth of subcutaneously implanted Capan-1 cells in SCID mice (p<0.05), the maximum growth inhibitory effect being observed in the first seven days after the start of treatment (p<0.005) with no additional effect noted thereafter (total duration of treatment=12 days). Thus, we show for the first time that FP represses the transcription of MUC4 oncoprotein while upregulating HER-2 in PC cells, an effect proportional to the expression of GRα by the cells. Significantly, FP treatment decreased the expression of N-cadherin by GRαhigh cells, suggesting a possible role as an inhibitor of metastases in PC. The increased HER-2 together with downregulation of MUC4 could increase the accessibility of HER-2 for therapy with drugs like Trastuzumab and Lapatinib. FP also increased sensitivity to Docetaxel and 5-FU, suggesting its potential utility as a selective chemosensitizing agent in anti-cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 722.