| Summary: | 博士 === 國立中正大學 === 分子生物研究所 === 104 === Cyproheptadine (CPH), a first-generation antihistamine, has recently been reported to function as a novel therapeutic agent in cancers, but never been explored in urothelial carcinoma (UC). In our study, we determined the effect of CPH on the growth of human bladder cell lines and an in vivo xenograft model. The results showed that CPH induced cell cycle arrest in the G0/G1 phase and exerted an inhibitory effect on cancer cells proliferation both in vitro and in vivo, subsequently followed by apoptosis and necrosis. The underlying mechanisms of cell cycle arrest in CPH-treated bladder cells were associated with the induction of p21 and p27, reduction of c-Myc and the stabilization of Rb expression. In addition, deregulation of the GSK3β/β-catenin signaling and the GSK3β/TSC2/mTOR pathway were observed. Furthermore, CPH-induced apoptosis was associated with overexpressed PPARγ and ANGPTL4 followed by activation of caspase3 and PARP in UC cells. Our results provide evidence that CPH is a potential therapeutic agent for the treatment of UC.
Previous studies had demonstrated that ANGPTL4 is highly expressed in some cancers, but downregulated, by DNA methylation, in others. Consequently, due these seemingly conflicting functions in distinct cancers, the precise role of ANGPTL4 in the etiology of UC remains unclear. In this study, we show that ANGPTL4 is transcriptionally repressed by DNA methylation in UC cell lines and primary tumor samples. Functional studies further demonstrated that ectopic expression of ANGPTL4 potently suppressed UC cell proliferation, monolayer colony formation in vitro, and xenograft formation in vivo. Interestingly, circulating ANGPTL4 (cANGPTL4) was detectable in plasma samples from UC patients, suggesting it could be used as a minimally invasive diagnostic marker. Interestingly, our data also indicated that exogenous cANGPTL4 could promote cell proliferation and cell migration via activation of signaling through the Erk/FAK axis. We further confirmed that mouse xenograft tumor growth could be promoted by administration of exogenous cANGPTL4. In conclusion, our data supports dual roles for ANGPTL4 in UC progression, either as a tumor suppressor or oncogene, in response to microenvironmental context.
Keywords: Cyproheptadine; mTOR signaling; ANGPTL4; Urothelial Carcinoma
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