Silencing of regulator of G‐protein signaling 10 (RGS10) increases phosphorylation of eukaryotic initiation factor 4E binding protein (4E‐BP1), and enhances growth and survival signaling pathways in ovarian cancer (843.11)

Abstract

Ovarian cancer is a devastating disease that is the 5th leading cause of cancer related deaths in women in the US. It is difficult to treat in that more than 70% of patients that are initially responsive to first‐line chemotherapeutics become refractory in less than 2 years. The problem of drug‐resistance or chemoresistance has plagued cancer researchers and hindered the success of cancer therapy development. In our previous studies examining computational bioinformatics, we demonstrated that reduced RGS gene expression develops with the occurrence of drug resistance in ovarian cancer cell lines. Specifically, we have shown that silencing of RGS10 protein increases viability of ovarian cancer cells in the presence of cycle arrest compounds such as paclitaxel. In our present study, we have shown that silencing RGS10 in ovarian cancer cell lines increases phosphorylation of Eukaryotic initiation factor (eLF) 4E, the mRNA 5’ cap‐binding protein (phosphorylated‐4E‐BP1). Phosphorylation of 4E‐BP1 has been shown to be a hallmark of more aggressive cancer phenotypes in prostate cancer and ovarian cancer. HeyA8 Parental and SKOV3 ovarian cancer cell lines were transiently transfected with siRNA non‐targeted control and human RGS10. Approximately 36 hrs post‐transfection cells were serum‐starved and treated with INK128 a selective mTOR inhibitor overnight. Cells were treated the following day with lysophosphatidic acid (LPA) and collected for western blot analysis. The same treatment conditions were also analyzed by immunofluorescence assays and imaged using a Cellomics ArrayScan VTI reader and HCS software. We found that when RGS10 was silenced in these ovarian cancer cell lines we observed changes in cell growth and size. Based on the results from these assays, we believe that we have elucidated a novel role of RGS10 in the growth and survival signaling pathways involved in the development of chemoresistance in ovarian cancer. Grant Funding Source: NIH