J Cancer 2021; 12(16):4862-4872. doi:10.7150/jca.58846

Research Paper

Exosomal IDH1 increases the resistance of colorectal cancer cells to 5-Fluorouracil

Hao Yang1,2✉, Sha Xie1, Beibei Liang1, Qiqi Tang1, Huanchen Liu1, Dongliang Wang1,2, Gang Huang1,2✉

1. Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China.
2. Department of Nuclear Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.

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Yang H, Xie S, Liang B, Tang Q, Liu H, Wang D, Huang G. Exosomal IDH1 increases the resistance of colorectal cancer cells to 5-Fluorouracil. J Cancer 2021; 12(16):4862-4872. doi:10.7150/jca.58846. Available from https://www.jcancer.org/v12p4862.htm

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Chemoresistance challenges the clinical treatment of colorectal cancer and requires an urgent solution. Isocitrate dehydrogenase 1 (IDH1) is a key enzyme involved in glucose metabolism that mediates the malignant transformation of tumors. However, the mechanisms by which IDH1 is involved in colorectal cancer cell proliferation and drug resistance induction remain unclear. In this study, we found that IDH1 was highly expressed in human colorectal cancer tissues and could be used to indicate a high-grade tumor. In vitro gene overexpression and knockdown were used to determine whether IDH1 promoted the proliferation of the colorectal cancer cell line HCT8 and resistance to 5-Fluorouracil (5FU). Further studies have shown that the 5FU-resistant cell line, HCT8FU, secreted exosomes that contained a high level of IDH1 protein. The exosomal IDH1 derived from 5FU-resistant cells enhanced the resistance of 5FU-sensitive cells. Metabolic assays revealed that exosomes derived from 5FU-resistant cells promoted a decrease in the level of IDH1-mediated NADPH, which is associated with the development of 5FU resistance in colorectal cancer cells. Therefore, exosomal IDH1 may be the transmitter and driver of chemoresistance in colorectal cancer and a potential chemotherapy target.

Keywords: colorectal cancer, 5-Fluorouracil, IDH1, exosomes