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

Oncogene (2021-05-16)
Jian Chen, Risi Na, Chao Xiao, Xiao Wang, Yupeng Wang, Dongwang Yan, Guohe Song, Xueni Liu, Jiayi Chen, Huijun Lu, Chunyan Chen, Huamei Tang, Guohong Zhuang, Guangjian Fan, Zhihai Peng
RESUMEN

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.

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Anti-β-actina, anticuerpo monoclonal, clone AC-15, purified from hybridoma cell culture
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Anti-LC3-I/II Antibody, from rabbit, purified by affinity chromatography
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