The loss of SHMT2 mediates 5-fluorouracil chemoresistance in colorectal cancer by upregulating autophagy
| العنوان: | The loss of SHMT2 mediates 5-fluorouracil chemoresistance in colorectal cancer by upregulating autophagy |
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| المؤلفون: | Xiao Wang, Huamei Tang, Jian Chen, Chao Xiao, Guohe Song, Guangjian Fan, Risi Na, Zhihai Peng, Dongwang Yan, Huijun Lu, Yupeng Wang, Xueni Liu, Chunyan Chen, Chen Jiayi, Guohong Zhuang |
| المصدر: | Oncogene |
| بيانات النشر: | Springer Science and Business Media LLC, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Antimetabolites, Antineoplastic, Cancer Research, Colorectal cancer, Cell, Regulator, Mice, Nude, Apoptosis, Biology, Article, Antimalarials, Mice, 03 medical and health sciences, 0302 clinical medicine, In vivo, Chloroquine, Cell Line, Tumor, Autophagy, Genetics, medicine, Animals, Humans, Molecular Biology, Cell Proliferation, Glycine Hydroxymethyltransferase, Mice, Inbred BALB C, medicine.disease, Xenograft Model Antitumor Assays, Survival Rate, 030104 developmental biology, medicine.anatomical_structure, Drug Resistance, Neoplasm, Fluorouracil, 030220 oncology & carcinogenesis, Cancer research, Female, Colorectal Neoplasms, Signal Transduction, medicine.drug |
| الوصف: | 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. |
| تدمد: | 1476-5594 0950-9232 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::89fa6918266c902988e6849237e17c34 https://doi.org/10.1038/s41388-021-01815-4 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....89fa6918266c902988e6849237e17c34 |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 14765594 09509232 |
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