Abstract
Abstract Human Sulfatase1 enzyme (HSulf-1) is down-regulated in a majority of ovarian cancer cell lines and primary tumors, but the functional consequence of this downregulation remains unclear. Here, we show that down-regulation of HSulf-1 by RNA interference resulted in an elevated level of phosphorylated Erk and phosphorqylated Akt as well as decreased Bim level in OV202 ovarian cancer cells. Treatment with PD98059 (p-Erk inhibitor) but not LY90024 (PI3K inhibitor) resulted in increased Bim level in Hsulf-1 knockdown cells, suggesting that increased Erk pathway plays a more important role in modulating Bim level after loss of HSulf-1. Consistently, the results of real-time PCR confirmed that there was no significant change in the mRNA level of Bim after knockdown of HSulf-1 expression. When treated with CDDP, OV202 cells with knockdown of HSulf-1 displayed more resistance to drug-induced apoptosis, with IC50 value 3-fold higher than cells with non-targeting shRNA (NTC), while SKOV3 cells with overexpression of HSulf-1 were more sensitive to CDDP-induced apoptosis compared to the control cells. Moreover, HSulf-1 downregulated OV202 cells showed remarkable growth of colonies in soft agar compared to no colony growing with NTC cells. When injected subcutaneously, HSulf-1 ShRNA clones but not NTC cells formed xenogrfts in nude mice. Importantly, rescuing Bim expression in HSulf-1 shRNA cells not only endowed cells sensitivity to CDDP treatment, but also significantly decreased numbers of colony formation in soft agar and significantly retarded tumor growth in nude mice. Collectively, these results strongly suggest that down-regulation of HSulf-1 promotes chemoresistance and tumorigenicity in ovarian cancer cells through post-translational downregulation of Bim level. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4179. doi:1538-7445.AM2012-4179
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