2. Academic Validation
  3. Knockdown of cytokeratin 8 overcomes chemoresistance of chordoma cells by aggravating endoplasmic reticulum stress through PERK/eIF2α arm of unfolded protein response and blocking autophagy

Knockdown of cytokeratin 8 overcomes chemoresistance of chordoma cells by aggravating endoplasmic reticulum stress through PERK/eIF2α arm of unfolded protein response and blocking autophagy

  • Cell Death Dis. 2019 Nov 25;10(12):887. doi: 10.1038/s41419-019-2125-9.
Di Wang 1,  Peiran Zhang 2,  Xiaolong Xu 1,  Jianhui Wang 1,  Dong Wang 1,  Pandi Peng 1 3,  Chao Zheng 1,  Qing-Jun Meng 4,  Liu Yang 5 6,  Zhuojing Luo 7 8
Affiliations

Affiliations

  • 1 Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
  • 2 Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, 710032, China.
  • 3 Medical Research Institute, Northwestern Polytechnical University, Xi'an, 710032, China.
  • 4 Wellcome Centre for Cell Matrix Research, Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
  • 5 Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China. yangliu@fmmu.edu.cn.
  • 6 Medical Research Institute, Northwestern Polytechnical University, Xi'an, 710032, China. yangliu@fmmu.edu.cn.
  • 7 Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China. zjluo@fmmu.edu.cn.
  • 8 Medical Research Institute, Northwestern Polytechnical University, Xi'an, 710032, China. zjluo@fmmu.edu.cn.
PMID: 31767864 DOI: 10.1038/s41419-019-2125-9
Abstract

Chordoma is a malignant primary osseous spinal tumor with pronounced chemoresistance. However, the mechanisms of how chordoma cells develop chemoresistance are still not fully understood. Cytokeratin 8 (KRT8) is a molecular marker of notochordal cells, from which chordoma cells were believed to be originated. In this study, we showed that either doxorubicin or irinotecan promoted KRT8 expression in both CM319 and UCH1 cell lines, accompanied by an increased unfolded protein response and Autophagy activity. Then, siRNA-mediated knockdown of KRT8 chemosensitized chordoma cells in vitro. Mechanistic studies showed that knockdown of KRT8 followed by chemotherapy aggravated endoplasmic reticulum stress through PERK/eIF2α arm of unfolded protein response and blocked late-stage Autophagy. Moreover, suppression of the PERK/eIF2α arm of unfolded protein response using PERK Inhibitor GSK2606414 partially rescued the apoptotic chordoma cells but did not reverse the blockage of the Autophagy flux. Finally, tumor xenograft model further confirmed the chemosensitizing effects of siKRT8. This study represents the first systematic investigation into the role of KRT8 in chemoresistance of chordoma and our results highlight a possible strategy of targeting KRT8 to overcome chordoma chemoresistance.

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