The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, China, 210093.
Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Medical School, Nanjing University, Nanjing, China, 210093.
Int J Biol Sci. 2021 Jul 2;17(11):2756-2769. doi: 10.7150/ijbs.59262. eCollection 2021.
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 () 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 promoted chemotherapy resistance of colon cancer to oxaliplatin. Compared with oxaliplatin-treated group, the expression of functional MMR proteins in tumors were decreased in oxaliplatin -treated group, while the glycolysis level of tumors was up-regulated and the production of lactate was significantly increased in oxaliplatin -treated group. Inhibiting lactate production significantly alleviated the chemoresistance and rescued the decreased expression of MMR caused by . Furthermore, we found that lactate down-regulated the expression of MLH1 through the GPR81-cAMP-PKA-CREB axis. This study clarified that promoted chemoresistance of colon cancer via producing lactate and inhibiting the expression of MLH1, which may provide novel ideas for improving CRC chemotherapy effect.
由于化疗药物耐药性，结直肠癌（CRC）患者肿瘤复发很常见，而耐药患者常伴有错配修复系统（MMR）缺陷。我们之前的研究表明，（）与结直肠癌的发生发展密切相关，但这种条件致病性真菌是否参与化疗需要进一步研究。在这里，我们发现（）促进了结直肠癌细胞对奥沙利铂的化疗耐药性。与奥沙利铂处理组相比，奥沙利铂处理组肿瘤中功能性 MMR 蛋白的表达降低，而肿瘤的糖酵解水平上调，乳酸的产生明显增加。抑制乳酸的产生显著缓解了耐药性，并挽救了由（）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。本研究阐明了（）通过产生乳酸和抑制 MLH1 的表达来促进结肠癌的化疗耐药性，这可能为提高 CRC 化疗效果提供新的思路。
