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
  • View Affiliations

  • 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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October 2017
Volume 38 Issue 4

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APA
Kobayashi, M., Kuroki, S., Kurita, S., Miyamoto, R., Tani, H., Tamura, K., & Bonkobara, M. (2017). 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, 38, 2543-2550. https://doi.org/10.3892/or.2017.5865
MLA
Kobayashi, M., Kuroki, S., Kurita, S., Miyamoto, R., Tani, H., Tamura, K., Bonkobara, M."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 38.4 (2017): 2543-2550.
Chicago
Kobayashi, M., Kuroki, S., Kurita, S., Miyamoto, R., Tani, H., Tamura, K., Bonkobara, M."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 38, no. 4 (2017): 2543-2550. https://doi.org/10.3892/or.2017.5865