Int J Biol Sci 2021; 17(11):2756-2769. doi:10.7150/ijbs.59262 This issue

Research Paper

C. tropicalis promotes chemotherapy resistance in colon cancer through increasing lactate production to regulate the mismatch repair system

Junxing Qu1,2, Zhiheng Sun1,2, Chen Peng1,2, Daoqian Li1,2, Wenyue Yan3, Zhen Xu1,2, Yayi Hou1,2, Sunan Shen1,2✉, Ping Chen3✉, Tingting Wang1,2✉

1. The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, China, 210093.
2. Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Medical School, Nanjing University, Nanjing, China, 210093.
3. Department of Oncology, Yancheng First Hospital, Affiliated Hospital of Nanjing University Medical School, The First People's Hospital of Yancheng, Yancheng, Jiangsu, China, 224001.

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Citation:
Qu J, Sun Z, Peng C, Li D, Yan W, Xu Z, Hou Y, Shen S, Chen P, Wang T. C. tropicalis promotes chemotherapy resistance in colon cancer through increasing lactate production to regulate the mismatch repair system. Int J Biol Sci 2021; 17(11):2756-2769. doi:10.7150/ijbs.59262. Available from https://www.ijbs.com/v17p2756.htm

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Abstract

Graphic abstract

Due to chemotherapeutic drug resistance, tumor recurrence is common in patients with colorectal cancer (CRC) and chemo-resistant patients are often accompanied by defects in the mismatch repair system (MMR). Our previous study has shown that Candida tropicalis (C. tropicalis) is closely related to the occurrence and development of colorectal cancer, but whether this conditional pathogenic fungus is involved in chemotherapy needs further investigation. Here we found that C. tropicalis promoted chemotherapy resistance of colon cancer to oxaliplatin. Compared with oxaliplatin-treated group, the expression of functional MMR proteins in tumors were decreased in C.tropicalis/oxaliplatin -treated group, while the glycolysis level of tumors was up-regulated and the production of lactate was significantly increased in C.tropicalis/oxaliplatin -treated group. Inhibiting lactate production significantly alleviated the chemoresistance and rescued the decreased expression of MMR caused by C. tropicalis. Furthermore, we found that lactate down-regulated the expression of MLH1 through the GPR81-cAMP-PKA-CREB axis. This study clarified that C. tropicalis promoted chemoresistance of colon cancer via producing lactate and inhibiting the expression of MLH1, which may provide novel ideas for improving CRC chemotherapy effect.

Keywords: Candida. tropicalis, chemoresistance, glycolysis, lactate, mismatch repair