Destruxin B inhibits hepatocellular carcinoma cell growth through modulation of the Wnt/尾-catenin signaling pathway and epithelial-mesenchymal transition

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• 作者：Thanh-Tuan Huynh^a ; ^b ; Yerra Koteswara Rao^c ; Wei-Hwa Lee^d ; Hsin-An Chen^e ; T. Do-Quyen Le^f ; David T.W. Tzeng^g ; Liang-Shun Wang^a ; ^h ; Alexander T.H. Wuⁱ ; Yuh-Feng Lin^a ; Yew-Min Tzeng^c ; ^{ymtzeng@cyut.edu.tw" class="auth_mail} ; Chi-Tai Yeh^a ; ^e ; ^j ; ^{ctyeh@tmu.edu.tw" class="auth_mail}
• 关键词：Destruxin B ; EMT ; HCC ; Metastasis ; Sorafenib combination ; Wnt/尾-catenin
• 刊名：Toxicology in Vitro
• 出版年：June, 2014
• 年：2014
• 卷：28
• 期：4
• 页码：552-561
• 全文大小：1970 K

文摘

The aberrant activation of Wnt/尾-catenin signaling plays an important role in the carcinogenesis and progression of hepatocellular carcinoma (HCC). Therefore, the Wnt/尾-catenin signaling molecules are attractive candidates for the development of targeted therapies for this disease. The present study showed that destruxin B (DB) inhibits the proliferation and induces the apoptosis of HCC cells by decreasing the protein expression of anti-apoptotic Bcl-2 and Bcl-xL and increasing the expression of the proapoptotic protein Bax. More importantly, DB also attenuates Wnt-signaling in HCC cells by downregulating 尾-catenin, Tcf4, and 尾-catenin/Tcf4 transcriptional activity, which results in the decreased expression of 尾-catenin target genes, such as cyclin D1, c-myc, and survivin. Furthermore, DB affects the migratory and invasive abilities of Sk-Hep1 cells through the suppression of markers of the epithelial-mesenchymal transition (EMT). A synergistic anti-proliferative and migratory effect was achieved using the combination of DB and sorafenib in Sk-Hep1 cells. In conclusion, DB acts as a novel Wnt/尾-catenin inhibitor and reduces the aggressiveness and invasive potential of HCC by altering the cells鈥?EMT status and mobility. DB in combination with sorafenib may be considered for future clinical use for the management of metastatic HCC.