XPO1 inhibitor KPT-330 synergizes with Bcl-xL inhibitor to induce cancer cell apoptosis by perturbing rRNA processing and Mcl-1 protein synthesis

  • Cell Death Dis. 2019 May 21;10(6):395. doi: 10.1038/s41419-019-1627-9.
Zhi-Chuan Zhu  1 ,  Ji-Wei Liu  2 ,  Can Yang  1  3 ,  Miao Zhao  4 ,  Zhi-Qi Xiong  5  6  7
Affiliations
  • 1. Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.
  • 2. Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3. University of Chinese Academy of Sciences, Beijing, China.
  • 4. Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
  • 5. Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 6. University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • 7. School of Life Science and Technology, ShanghaiTech University, Shanghai, China. [email protected].
PMID: 31113936 DOI: 10.1038/s41419-019-1627-9
Abstract

XPO1 (exportin1) mediates nuclear export of proteins and RNAs and is frequently overexpressed in cancers. In this study, we show that the orally bioavailable XPO1 inhibitor KPT-330 reduced Mcl-1 protein level, by which it synergized with Bcl-xL Inhibitor A-1331852 to induce Apoptosis in Cancer cells. KPT-330/A-1331852 combination disrupted bindings of Mcl-1 and Bcl-xL to Bax, Bak, and/or Bim, elicited mitochondrial outer membrane permeabilization, and triggered Apoptosis. KPT-330 generally mitigated mRNA expression and protein synthesis rather than mRNA nuclear export or protein stability of Mcl-1. KPT-330 inhibited mTORC1/4E-BP1 and MNK1/eIF4E axes, which disrupted the eIF4F translation initiation complex but was dispensable for Mcl-1 reduction and KPT-330/A-1331852 combination-induced Apoptosis. Mature rRNAs are integral components of the ribosome that determines protein synthesis ability. KPT-330 impeded nucleolar rRNA processing and reduced total levels of multiple mature rRNAs. Reconstitution of XPO1 by expressing degradation-resistant C528S mutant retained rRNA amount, Mcl-1 expression, and Bcl-xL Inhibitor resistance upon KPT-330 treatment. KPT-330/A-1331852 combination suppressed growth and enhanced Apoptosis of non-small cell lung Cancer xenografts. Therefore, we clarify the reason of Apoptosis resistance of Cancer cells to XPO1 inhibition and develop a potential strategy for treating solid tumors.

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