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

ABSTRACT: 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.

SUBMITTER: Chen J

PROVIDER: S-EPMC8195740 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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

Chen Jian J Na Risi R Xiao Chao C Wang Xiao X Wang Yupeng Y Yan Dongwang D Song Guohe G Liu Xueni X Chen Jiayi J Lu Huijun H Chen Chunyan C Tang Huamei H Zhuang Guohong G Fan Guangjian G Peng Zhihai Z

Oncogene 20210514 23

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 ...[more]

PMID: 33990700

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Project description:BackgroundColorectal cancer (CRC) is the third major cause of cancer-related death worldwide, and fluorouracil (5-FU) is widely used in the treatment of CRC. However, acquired resistance to 5-FU has become an obstacle in the effective treatment of CRC. Adenosine triphosphate (ATP)-binding cassette sub-family G member 2 (ABCG2) has been found highly expressed in CRC patients with poor responsiveness to folinic acid/5-FU/irinotecan. However, the mechanisms of 5-FU resistance regulated by ABCG2 in CRC cells remain to be comprehensively understood. We aimed to explore the upstream mechanisms of ABCG2 involved in the regulation of chemoresistance in CRC cells.MethodsWe investigated the potential mechanisms of 5-FU resistance in HCT116, RKO, RKO microRNA-21 (miR-21) knockout, and acquired 5-FU-resistant HCT116 (HCT116/FUR) cells. The biochemical and biological analyses were conducted using semiquantitative reverse transcription-polymerase chain reaction (qRT-PCR), western blotting, transfections, and rescue experiments, along with cell proliferation, viability, and colony formation assays. In order to investigate the efficacy of inhibiting the c-Jun NH2 terminal kinase (JNK) pathway to overcome 5-FU resistance, HCT116 and 5-FU-resistant HCT116 cells were inoculated into BALB/c-nu/nu mice to establish the cell-derived xenograft model.ResultsThe results showed that ABCG2 expression in HCT116/FUR cells was higher compared to HCT116 cells. Overexpression of ABCG2 decreased sensitivity to 5-FU in HCT116 cells, but knockdown of ABCG2 decreased the survival rate in HCT116/FUR cells. Additionally, repressing programmed cell death 4 (PDCD4) activated the JNK pathway in HCT116/FUR cells. Overexpression of PDCD4 inhibited phosphorylation of c-Jun and ABCG2 expression, and recovered sensitivity to 5-FU in HCT116/FUR cells. Moreover, treatment with the JNK pathway inhibitor SP600125 downregulated ABCG2 expression and rescued sensitivity to 5-FU in HCT116/FUR cells. We also found that miR-21 expression in HCT116/FUR cells was higher compared to HCT116 cells. Finally, 5-FU treatment in combination with SP600125 significantly decreased tumorigenicity compared to other treatments in vivo.ConclusionsOur results demonstrated that 5-FU treatment upregulated miR-21, which directly repressed PDCD4, and subsequently activated the JNK pathway, leading to the upregulation of ABCG2 in CRC cells. Inhibition of the JNK pathway overcame acquired 5-FU resistance both in vivo and in vitro.

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

Publications

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

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