1. Academic Validation
  2. Lanatoside C inhibits cell proliferation and induces apoptosis through attenuating Wnt/β-catenin/c-Myc signaling pathway in human gastric cancer cell

Lanatoside C inhibits cell proliferation and induces apoptosis through attenuating Wnt/β-catenin/c-Myc signaling pathway in human gastric cancer cell

  • Biochem Pharmacol. 2018 Apr;150:280-292. doi: 10.1016/j.bcp.2018.02.023.
Yudong Hu 1 Kaikai Yu 2 Gang Wang 3 Depeng Zhang 4 Chaoji Shi 5 Yunhe Ding 6 Duo Hong 7 Dan Zhang 8 Huiqiong He 9 Lei Sun 10 Jun-Nian Zheng 11 Shuyang Sun 12 Feng Qian 13
Affiliations

Affiliations

  • 1 Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, PR China. Electronic address: [email protected].
  • 2 Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, PR China. Electronic address: [email protected].
  • 3 Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou 221004, PR China. Electronic address: [email protected].
  • 4 Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, PR China. Electronic address: [email protected].
  • 5 Department of Oral and Maxillofacial-Head Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200011, PR China. Electronic address: [email protected].
  • 6 Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, PR China. Electronic address: [email protected].
  • 7 Department of Oral and Maxillofacial-Head Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200011, PR China. Electronic address: [email protected].
  • 8 Research Center for Cancer Precision Medicine, Department of Laboratory Medicine, Bengbu Medical College, Bengbu 233030, PR China.
  • 9 Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, PR China. Electronic address: [email protected].
  • 10 Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, PR China. Electronic address: [email protected].
  • 11 Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou 221004, PR China. Electronic address: [email protected].
  • 12 Department of Oral and Maxillofacial-Head Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200011, PR China. Electronic address: [email protected].
  • 13 Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, PR China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou 221004, PR China; Research Center for Cancer Precision Medicine, Department of Laboratory Medicine, Bengbu Medical College, Bengbu 233030, PR China. Electronic address: [email protected].
Abstract

Gastric Cancer is the third common cause of Cancer mortality in the world with poor prognosis and high recurrence due to lack of effective medicines. Our studies revealed that lanatoside C, a FDA-approved cardiac glycoside, had an anti-proliferation effect on different human Cancer cell lines (MKN-45; SGC-7901; HN4; MCF-7; HepG2) and gastric cell lines MKN-45 and SGC-7901 were the most sensitive cell lines to lanatoside C. MKN-45 cells treated with lanatoside C showed cell cycle arrest at G2/M phase and inhibition of cell migration. Meanwhile, upregulation of cleaved caspase-9 and cleaved PARP and downregulation of Bcl-xL were accompanied with the loss of mitochondrial membrane potential (MMP) and induction of intracellular Reactive Oxygen Species (ROS). Lanatoside C inhibited Wnt/β-catenin signaling with downregulation of c-Myc, while overexpression of c-Myc reversed the anti-tumor effect of lanatoside C, confirming that c-Myc is a key drug target of lanatoside C. Furthermore, we discovered that lanatoside C prompted c-Myc degradation in proteasome-ubiquitin pathway with attenuating the binding of USP28 to c-Myc. These findings indicate that lanatoside C targeted c-Myc ubiquitination to inhibit MKN-45 proliferation and support the potential value of lanatoside C as a chemotherapeutic candidate.

Keywords

Gastric cancer; Lanatoside C; Ubiquitination; c-Myc; β-Catenin.

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