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.

中文翻译：

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C.tropicalis 通过增加乳酸产生以调节错配修复系统来促进结肠癌的化疗耐药性

由于化疗药物的耐药性，结直肠癌（CRC）患者的肿瘤复发很常见，而化疗耐药的患者通常伴有错配修复系统（MMR）的缺陷。我们前期的研究表明，热带念珠菌（C.tropicalis）与大肠癌的发生、发展密切相关，但这种条件性致病菌是否与化疗有关还有待进一步研究。在这里，我们发现C.tropicalis促进了结肠癌对奥沙利铂的化疗耐药性。与奥沙利铂治疗组相比，C.tropicalis/肿瘤中功能性MMR蛋白的表达降低。奥沙利铂治疗组肿瘤的糖酵解水平上调，乳酸的产生显着增加。抑制乳酸产生显着减轻了化学抗性并挽救了由热带念珠菌引起的MMR表达降低。此外，我们发现乳酸通过 GPR81-cAMP-PKA-CREB ​​轴下调 MLH1 的表达。本研究阐明热带假丝酵母通过产生乳酸和抑制MLH1的表达来促进结肠癌的化疗耐药，这可能为提高CRC化疗效果提供新的思路。