The loss of SHMT2 mediates 5-fluorouracil chemoresistance in colorectal cancer by upregulating autophagy

• Published in: Oncogene Vol. 40; no. 23; pp. 3974 - 3988
• Main Authors: Chen, Jian, Na, Risi, Xiao, Chao, Wang, Xiao, Wang, Yupeng, Yan, Dongwang, Song, Guohe, Liu, Xueni, Chen, Jiayi, Lu, Huijun, Chen, Chunyan, Tang, Huamei, Zhuang, Guohong, Fan, Guangjian, Peng, Zhihai
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10-06-2021; Nature Publishing Group
• Subjects: 13/21; 14; 14/1; 38; 38/77; 42; 5-Fluorouracil; 631/67/1504/1885; 631/80/82/39; 64; 64/60; 96; Animals; Antimalarials - pharmacology; Antimetabolites, Antineoplastic - pharmacology; Apoptosis; Apoptosis - drug effects; Autophagy; Autophagy (Cytology); Autophagy - drug effects; Cell Biology; Cell culture; Cell Line, Tumor; Cell Proliferation - drug effects; Chemoresistance; Chemotherapy; Chloroquine; Chloroquine - pharmacology; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Development and progression; Drug resistance; Drug Resistance, Neoplasm; Drug therapy; Female; Fluorouracil; Fluorouracil - pharmacology; Genetic aspects; Genetic regulation; Glycine Hydroxymethyltransferase - deficiency; Glycine Hydroxymethyltransferase - metabolism; Health aspects; Human Genetics; Humans; Internal Medicine; Lethality; Medicine; Medicine & Public Health; Methyltransferases; Mice; Mice, Inbred BALB C; Mice, Nude; Oncology; Patient outcomes; Phagocytosis; Serine; Signal Transduction; Survival Rate; Xenograft Model Antitumor Assays; Xenografts; China
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-021-01815-4

5-Fluorouracil (5-FU)-based chemotherapy is the first-line treatment for colorectal cancer (CRC) but is hampered by chemoresistance. Despite its impact on patient survival, the mechanism underlying chemoresistance against 5-FU remains poorly understood. Here, we identified serine hydroxymethyltransferase-2 (SHMT2) as a critical regulator of 5-FU chemoresistance in CRC. SHMT2 inhibits autophagy by binding cytosolic p53 instead of metabolism. SHMT2 prevents cytosolic p53 degradation by inhibiting the binding of p53 and HDM2. Under 5-FU treatment, SHMT2 depletion promotes autophagy and inhibits apoptosis. Autophagy inhibitors decrease low SHMT2-induced 5-FU resistance in vitro and in vivo. Finally, the lethality of 5-FU treatment to CRC cells was enhanced by treatment with the autophagy inhibitor chloroquine in patient-derived and CRC cell xenograft models. Taken together, our findings indicate that autophagy induced by low SHMT2 levels mediates 5-FU resistance in CRC. These results reveal the SHMT2–p53 interaction as a novel therapeutic target and provide a potential opportunity to reduce chemoresistance.