Acquisition of chemoresistance to gemcitabine is induced by a loss-of-function missense mutation of DCK

Tomohiro Nakano, Yuriko Saiki, Chiharu Kudo, Akiyoshi Hirayama, Yasuhiko Mizuguchi, Sho Fujiwara, Tomoyoshi Soga, Makoto Sunamura, Nobutoshi Matsumura, Fuyuhiko Motoi, Michiaki Unno, Akira Horii

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11 Citations (Scopus)

Abstract

The anti-tumor activity of gemcitabine (GEM) has been clinically proven in several solid tumors, including pancreatic cancer, biliary tract cancer, urinary bladder cancer, and non-small cell lung cancer. However, problems remain with issues such as acquisition of chemoresistance against GEM. GEM is activated after phosphorylation by deoxycytidine kinase (DCK) inside of the cell; thus, DCK inactivation is one of the important mechanisms for acquisition of GEM resistance. We previously investigated the DCK gene in multiple GEM resistant cancer cell lines and identified frequent inactivating mutations. In this study, we identified two crucial genetic alteration in DCK. (1) A total deletion of DCK in RTGBC1-TKB, an acquired GEM resistant cell line derived from a gall bladder cancer cell line TGBC1-TKB. (2) An E197K missense alteration of DCK in MKN28, a gastric cancer cell line; its acquired GEM resistant cancer cell line, RMKN28, showed a loss of the normal E197 allele. We introduced either normal DCK or altered DCK-E197K into RMKN28 and proved that only the introduction of normal DCK restored GEM sensitivity. Furthermore, we analyzed 104 healthy volunteers and found that none of them carried the same base substitution observed in MKN28. These results strongly suggest that (1) the E197K alteration in DCK causes inactivation of DCK, and that (2) loss of the normal E197 allele is the crucial mechanism in acquisition of GEM resistance in RMKN28.

Original languageEnglish
Pages (from-to)1084-1089
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume464
Issue number4
DOIs
Publication statusPublished - 2015 Sep 4

Keywords

  • Chemoresistance
  • Deoxycytidine kinase
  • Gemcitabine
  • MKN28
  • TGBC1-TKB

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Nakano, T., Saiki, Y., Kudo, C., Hirayama, A., Mizuguchi, Y., Fujiwara, S., Soga, T., Sunamura, M., Matsumura, N., Motoi, F., Unno, M., & Horii, A. (2015). Acquisition of chemoresistance to gemcitabine is induced by a loss-of-function missense mutation of DCK. Biochemical and Biophysical Research Communications, 464(4), 1084-1089. https://doi.org/10.1016/j.bbrc.2015.07.080