Abstract
Ovarian cancer is the deadliest of gynecologic cancers, largely due to the development of drug resistance in chemotherapy. Prostasin may have an essential role in the oncogenesis. In this study, we show that prostasin is decreased in an ovarian cancer drug-resistant cell line and in ovarian cancer patients with high levels of excision repair cross-complementing 1, a marker for chemoresistance. Our cell cultural model investigation demonstrates prostasin has important roles in the development of drug resistance and cancer cell survival. Forced overexpression of prostasin in ovarian cancer cells greatly induces cell death (resulting in 99% cell death in a drug-resistant cell line and 100% cell death in other tested cell lines). In addition, the surviving cells grow at a much lower rate compared with non-overexpressed cells. In vivo studies indicate that forced overexpression of prostasin in drug-resistant cells greatly inhibits the growth of tumors and may partially reverse drug resistance. Our investigation of the molecular mechanisms suggests that prostasin may repress cancer cells and/or contribute to chemoresistance by modulating the CASP/P21-activated protein kinase (PAK2)-p34 pathway, and thereafter PAK2-p34/JNK/c-jun and PAK2-p34/mlck/actin signaling pathways. Thus, we introduce prostain as a potential target for treating/repressing some ovarian tumors and have begun to identify their relevant molecular targets in specific signaling pathways.
Highlights
Ovarian cancer is the deadliest of gynecologic cancers, largely due to the development of drug resistance in chemotherapy and late-stage diagnosis
We proposed that prostasin may have role in chemoresistance because it is malexpressed in various types of cancers.[8,9,10,11]
Real-time quantitative PCR data showed that prostasin expression was significantly lower in tumor samples from excision repair cross-complementing 1 (ERCC1)-high group (n 1⁄4 18), compared with ERCC1-low group (n 1⁄4 31), and that prostasin mRNA is greatly reduced in potentially chemoresistant tumors compared with chemosensitive tumors (Figure 1a, Po0.01)
Summary
Ovarian cancer is the deadliest of gynecologic cancers, largely due to the development of drug resistance in chemotherapy and late-stage diagnosis. Prostasin is termed channel-activating protease 1, which is implicated in the regulation of sodium and fluid levels via proteolysis of the epithelial sodium channel, and has important functions in blood pressure being a target for regulating hypertension.[15,16,17] In addition, prostasin has been found to have important roles in the epidermal barrier function, skin phenotypes, and embryonic viability.[18,19] prostasin is implicated in a wide spectrum of physiological and pathophysiological conditions.
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