A novel curcumin derivative CL-6 exerts antitumor effect in human gastric cancer cells by inducing apoptosis through Hippo–YAP signaling pathway

Chenmin Ye,1,2,* Wenqian Wang,3,* Guojun Xia,1,2,* Chengyang Yu,1,2 Yongdong Yi,1,2 Chunyan Hua,4 Fuyang Tu,1,2 Leibin Shen,1,2 Canjin Chen,1,2 Weijian Sun,1 Zhiqiang Zheng1 1Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325027, People’s Republic of China; 2The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province 325027, People’s Republic of China; 3Department of Breast Surgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325027, People’s Republic of China; 4School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang Province 325035, People’s Republic of China *These authors contributed equally to this work Purpose: Gastric carcinoma is the second most frequently diagnosed cancer and leading cause of cancer death in China. As a new generation of cancer therapeutic drug, CL-6, a curcumin derivative, shows better bioavailability than curcumin, which has shown anticancer effects in gastric cancer (GC). However, whether CL-6 shows similar activities in GC has not been examined. Materials and methods: Cell proliferation assay, colony-forming assay, flow cytometric analysis, wound healing assay, and Transwell invasion assay were performed to examine the effects of CL-6 on proliferation, apoptosis, migration, and invasion on human AGS and MGC-803 cell lines. Western blot was used to evaluate protein levels of Bax, Bcl-2, YAP, p-YAP, and Lats, and gene expression was measured by real-time quantitative PCR (RT-qPCR). Results: CL-6 dose dependently reduced proliferation, increased apoptosis, and inhibited the migration and invasion abilities of AGS and MGC-803 cells. CL-6 also increased levels of pro-apoptotic protein Bax, decreased levels of antiapoptotic protein Bcl-2, and increased the Bax/Bcl-2 ratio. CL-6 treatment also inhibited YAP and YAP protein and mRNA expression, while it induced the expression of Lats and p-YAP (Ser127). Conclusion: CL-6 induces apoptosis of GC cells by activating the Hippo–YAP signaling pathway. These results indicate the therapeutic potential of the novel curcumin derivative CL-6 in GC. Keywords: gastric cancer, apoptosis, migration, YAP, Hippo–YAP pathwa