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

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.

Mycobiota and C-Type Lectin Receptors in Cancers: Know thy Neighbors

“…CARD9 –/– mice have impaired fungicidal abilities, which led to increased fungal burden and MDSCs accumulation, inhibition of effector T cells, and the promotion of CRC development ( Wang T. et al, 2018 ; Figure 4 ). Moreover, the team also recently revealed that C. tropicalis induced chemotherapy resistance in CRC via increasing lactate production to regulate the mismatch repair system ( Qu et al, 2021 ). Coincidentally, research by Malik et al (2018) was also published in the same issue of immunity.…”

Lactate-derived HDAC6 Lactylation as a new target for neuronal protection in cerebral ischemic reperfusion injury

“…Mice subjected to tMCAO were randomly divided into each group. Oxamate (Selleck) was administered 500mg/kg intraperitoneally (Qu et al , 2021) at the onset of reperfusion. Mice in the sham group were injected with an equal amount of DMSO.…”

Lactate-related metabolic reprogramming and immune regulation in colorectal cancer

“…In general, patients with chemotherapy resistance are often accompanied by mismatch repair system (MMR) defects. Qu discoverd that lactic acid fermented by Clostridium tropicalis can enhance oxaliplatin tolerance in colon cancer patients, and targeted therapies that inhibit this metabolic pathway can significantly improve chemotherapy tolerance and MMR expression in vivo ( 111 ). Targeted inhibition of lactate production metabolism can significantly improve chemotherapy tolerance and reduce MMR expression.…”