Calyxin Y sensitizes cisplatin-sensitive and resistant hepatocellular carcinoma cells to cisplatin through apoptotic and autophagic cell death via SCF βTrCP-mediated eEF2K degradation

// Chao Zhang 1, * , Jian-Li Lei 1, * , Hao Zhang 1 , Yuan-Zheng Xia 1 , Pei Yu 1 , Lei Yang 1 and Ling-Yi Kong 1 1 Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China * These authors have contributed equally to this article Correspondence to: Ling-yi Kong, email: cpu_lykong@126.com Keywords: calyxin Y, cisplatin, eEF2K, autophagic and apoptotic cell death, HCC Received: May 27, 2017     Accepted: July 12, 2017     Published: August 03, 2017 ABSTRACT The down-regulation of eukaryotic elongation factor-2 kinase (eEF2K) is associated with an enhancement in the sensitivity of malignant cells to chemotherapeutic agents. In this study, we found that the silencing of eEF2K enhanced cisplatin (CDDP)-induced cytotoxicity in CDDP-sensitive (HepG2) and resistant (HepG2/CDDP) cells. Calyxin Y, a unique chalcone diarylheptanoid adduct, down-regulated eEF2K by promoting Skp1-Cul1-F-box protein (SCF) β-transducin repeat-containing protein (βTrCP)-mediated protein degradation and synergistically enhanced the cytotoxicity of CDDP. Subsequently, we identified a potential mechanism of this cooperative interaction by showing that the combination of calyxin Y and CDDP enhanced apoptotic cell death via mitochondrial dysfunction. In addition, the combination induced autophagy, which contributed to the synergistic cytotoxic effect. Further research revealed that calyxin Y synergistically sensitized HepG2 and HepG2/CDDP cells to CDDP through enhanced apoptotic and autophagic cell death via the SCF βTrCP-eEF2K pathway. Finally, in vivo studies demonstrated that calyxin Y could enhance the response of HepG2/CDDP cells to CDDP in xenograft models with low systemic toxicity. Thus, the combination of calyxin Y and CDDP might represent an attractive therapeutic strategy for the treatment of chemotherapy-sensitive and resistant hepatocellular carcinoma cells.