Oncotarget

Research Papers:

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, Jian-Li Lei, Hao Zhang, Yuan-Zheng Xia, Pei Yu, Lei Yang and Ling-Yi Kong _

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Oncotarget. 2017; 8:70595-70616. https://doi.org/10.18632/oncotarget.19883

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Abstract

Chao Zhang1,*, Jian-Li Lei1,*, Hao Zhang1, Yuan-Zheng Xia1, Pei Yu1, Lei Yang1 and Ling-Yi Kong1

1Jiangsu 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: [email protected]

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.


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