論文

査読有り
2017年10月

A decrease in ubiquitination and resulting prolonged life-span of KIT underlies the KIT overexpression-mediated imatinib resistance of KIT mutation-driven canine mast cell tumor cells

ONCOLOGY REPORTS
  • Masato Kobayashi
  • ,
  • Shiori Kuroki
  • ,
  • Sena Kurita
  • ,
  • Ryo Miyamoto
  • ,
  • Hiroyuki Tani
  • ,
  • Kyoichi Tamura
  • ,
  • Makoto Bonkobara

38
4
開始ページ
2543
終了ページ
2550
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.3892/or.2017.5865
出版者・発行元
SPANDIDOS PUBL LTD

Overexpression of KIT is one of the mechanisms that contributes to imatinib resistance in KIT mutation-driven tumors. Here, the mechanism underlying this overexpression of KIT was investigated using an imatinib-sensitive canine mast cell tumor (MCT) line CoMS, which has an activating mutation in KIT exon 11. A KIT-overexpressing imatinib-resistant subline, rCoMS1, was generated from CoMS cells by their continuous exposure to increasing concentrations of imatinib. Neither a secondary mutation nor upregulated transcription of KIT was detected in rCoMS1 cells. A decrease in KIT ubiquitination, a prolonged KIT life-span, and KIT overexpression were found in rCoMS1 cells. These events were suppressed by withdrawal of imatinib and were re-induced by re-treatment with imatinib. These findings suggest that imatinib elicited overexpression of KIT via suppression of its ubiquitination. These results also indicated that imatinib-induced overexpression of KIT in rCoMS1 cells was not a permanently acquired feature but was a reversible response of the cells. Moreover, the pan deubiquitinating enzyme inhibitor PR619 prevented imatinib induction of KIT overexpression, suggesting that the imatinib-induced decrease in KIT ubiquitination could be mediated by upregulation and/or activation of deubiquitinating enzyme(s). It may be possible that a similar mechanism of KIT overexpression underlies the acquisition of imatinib resistance in some human tumors that are driven by KIT mutation.


リンク情報
DOI
https://doi.org/10.3892/or.2017.5865
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/28765927
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000411688200074&DestApp=WOS_CPL