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IDH1‐mutant cancer cells are sensitive to cisplatin and an IDH1‐mutant inhibitor counteracts this sensitivity
Author(s) -
Khurshed Mohammed,
Aarnoudse Niels,
Hulsbos Renske,
Hira Vashendriya V. V.,
Laarhoven Hanneke W. M.,
Wilmink Johanna W.,
Molenaar Remco J.,
Noorden Cornelis J. F.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201800547r
Subject(s) - cisplatin , oxidative stress , cancer cell , isocitrate dehydrogenase , reactive oxygen species , dna damage , idh1 , programmed cell death , cancer research , microbiology and biotechnology , biology , glioma , cancer , mutant , chemistry , apoptosis , biochemistry , enzyme , chemotherapy , dna , gene , genetics
Isocitrate dehydrogenase (IDH1)‐1 is mutated in various types of human cancer, and the presence of this mutation is associated with improved responses to irradiation and chemotherapy in solid tumor cells. Mutated IDH1 (IDH1 MUT ) enzymes consume NADPH to produce D‐2‐hydroxyglutarate (D‐2HG) resulting in the decreased re ducing power needed for detoxification of reactive oxygen species (ROS), for example. The objective of the current study was to investigate the mechanism behind the chemosensitivity of the widely used anticancer agent cisplatin in IDH1 MUT cancer cells. Oxidative stress, DNA damage, and mitochondrial dysfunction caused by cisplatin treatment were monitored in IDH1 MUT HCT116 colorectal cancer cells and U251 glioma cells. We found that exposure to cisplatin induced higher levels of ROS, DNA double‐strand breaks (DSBS), and cell death in IDH1 MUT cancer cells, as compared with IDH1 wild‐type (IDH1 WT ) cells. Mechanistic investigations revealed that cisplatin treatment dose dependently reduced oxidative respiration in IDH1 MUT cells, which was accompanied by disturbed mitochondrial proteostasis, indicative of impaired mitochondrial activity. These effects were abolished by the IDH1 MUT inhibitor AGI‐5198 and were restored by treatment with D‐2HG. Thus, our study shows that altered oxidative stress responses and a vulnerable oxidative metabolism underlie the sensitivity of IDH1 MUT cancer cells to cisplatin.—Khurshed, M., Aarnoudse, N., Hulsbos, R., Hira, V. V. V., van Laarhoven, H. W. M., Wilmink, J. W., Molenaar, R. J., van Noorden, C. J. F. IDH1‐mutant cancer cells are sensitive to cisplatin and an IDH1‐mutant inhibitor counteracts this sensitivity. 32, 6344–6352 (2018). www.fasebj.org