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

Kobayashi,Masato; Kuroki,Shiori; Kurita,Sena; Miyamoto,Ryo; Tani,Hiroyuki; Tamura,Kyoichi; Bonkobara,Makoto

doi:10.3892/or.2017.5865

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

Authors:
- Masato Kobayashi
- Shiori Kuroki
- Sena Kurita
- Ryo Miyamoto
- Hiroyuki Tani
- Kyoichi Tamura
- Makoto Bonkobara
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Affiliations: Department of Veterinary Clinical Pathology, Nippon Veterinary and Life Science University, Kyonan-cho, Musashino-shi, Tokyo 180-8602, Japan
Published online on: August 1, 2017 https://doi.org/10.3892/or.2017.5865
Pages: 2543-2550

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Abstract

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.

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