Huynh Thanh-Tuan, Rao Yerra Koteswara, Lee Wei-Hwa, Chen Hsin-An, Le T Do-Quyen, Tzeng David T W, Wang Liang-Shun, Wu Alexander T H, Lin Yuh-Feng, Tzeng Yew-Min, Yeh Chi-Tai
Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan; Department of Neurosurgery, University of Medicine and Pharmacy, Ho Chi Minh City, Viet Nam.
Institute of Biochemical Sciences and Technology, Chaoyang University of Technology, Taichung, Taiwan.
Toxicol In Vitro. 2014 Jun;28(4):552-61. doi: 10.1016/j.tiv.2014.01.002. Epub 2014 Jan 13.
The aberrant activation of Wnt/β-catenin signaling plays an important role in the carcinogenesis and progression of hepatocellular carcinoma (HCC). Therefore, the Wnt/β-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 β-catenin, Tcf4, and β-catenin/Tcf4 transcriptional activity, which results in the decreased expression of β-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/β-catenin inhibitor and reduces the aggressiveness and invasive potential of HCC by altering the cells' EMT status and mobility. DB in combination with sorafenib may be considered for future clinical use for the management of metastatic HCC.
Wnt/β-连环蛋白信号通路的异常激活在肝细胞癌（HCC）的发生和发展中起重要作用。因此，Wnt/β-连环蛋白信号分子是开发该疾病靶向治疗药物的有吸引力的候选靶点。本研究表明，白僵菌素B（DB）通过降低抗凋亡蛋白Bcl-2和Bcl-xL的蛋白表达以及增加促凋亡蛋白Bax的表达来抑制HCC细胞的增殖并诱导其凋亡。更重要的是，DB还通过下调β-连环蛋白、Tcf4以及β-连环蛋白/Tcf4转录活性来减弱HCC细胞中的Wnt信号，这导致β-连环蛋白靶基因（如细胞周期蛋白D1、c-myc和存活素）的表达降低。此外，DB通过抑制上皮-间质转化（EMT）标志物来影响Sk-Hep1细胞的迁移和侵袭能力。在Sk-Hep1细胞中，DB与索拉非尼联合使用可产生协同的抗增殖和迁移作用。总之，DB作为一种新型的Wnt/β-连环蛋白抑制剂，通过改变细胞的EMT状态和迁移能力来降低HCC的侵袭性和转移潜能。DB与索拉非尼联合使用可能在未来临床中用于治疗转移性HCC。
