Abstract 2591: Folate receptor alpha: A promoter of cancer cell proliferation that is independent of folate

Abstract

Abstract Folate receptor alpha (FRα) is over-expressed in malignant tumors of epithelial origin, particularly in ovarian cancer, but largely absent in normal tissue. High levels of protein expression in tumor cells are associated with increased proliferative capacity and enhanced chemo-resistance to Cisplatinum (CP). However, the underlying mechanism remains unclear. We sought to evaluate the biological function of FRα in CP-resistant cancer and hypothesized that alterations of FRα expression levels in drug CP-resistant cancers would result in the re-sensitization of tumor cells to CP. We first developed a human ovarian cancer cell line, IGROV-1, with increased CP resistance and found that these cells also showed an increase in FRα expression over parental IGROV-1 cells. Then, we used FOLR1 specific siRNA to completely knock-down FRα expression. Surprisingly, ablation of FRα expression did not restore sensitivity to CP but had a substantial negative impact on proliferation in both parental and CP-resistant cells. Similar phenomena were also observed when FRα was knocked-down in 786-0 cells, a human renal carcinoma line that expresses robust levels of FRα. In contrast, when we applied FRα knock-down to the normal human kidney cells HK-2 (FRα+), we observed no impairment on proliferation. One explanation of these results is that removal of FRα in cancer cells impairs the ability of these cells to uptake reduced folates, a requirement for nucleic acid synthesis and other methylation reactions. However, even pharmacological concentrations of 5-methyltetrahydrofolate, provided only partial restoration of proliferation in these cells. Taken together, these results suggest that FRα plays an essential role in the proliferation of tumor cells, but not in normal cells via a yet undefined pathway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2591. doi:10.1158/1538-7445.AM2011-2591