MAPK Signaling‐Mediated RFNG Phosphorylation and Nuclear Translocation Restrain Oxaliplatin‐Induced Apoptosis and Ferroptosis
Abstract Chemotherapy resistance remains a major challenge in the treatment of colorectal cancer (CRC). Therefore, it is crucial to develop novel strategies to sensitize cancer cells to chemotherapy. Here, the fringe family is screened to determine their contribution to chemotherapy resistance in CR...
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Wiley
2024-10-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202402795 |
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| author | Yuqin Di Xiang Zhang Xiangqiong Wen Jiale Qin Lvlan Ye Youpeng Wang Mei Song Ziyang Wang Weiling He |
| author_facet | Yuqin Di Xiang Zhang Xiangqiong Wen Jiale Qin Lvlan Ye Youpeng Wang Mei Song Ziyang Wang Weiling He |
| author_sort | Yuqin Di |
| collection | DOAJ |
| description | Abstract Chemotherapy resistance remains a major challenge in the treatment of colorectal cancer (CRC). Therefore, it is crucial to develop novel strategies to sensitize cancer cells to chemotherapy. Here, the fringe family is screened to determine their contribution to chemotherapy resistance in CRC. It is found that RFNG depletion significantly sensitizes cancer cells to oxaliplatin treatment. Mechanistically, chemotherapy‐activated MAPK signaling induces ERK to phosphorylate RFNG Ser255 residue. Phosphorylated RFNG S255 (pS255) interacts with the nuclear importin proteins KPNA1/importin‐α1 and KPNB1/importin‐β1, leading to its translocation into the nucleus where it targets p53 and inhibits its phosphorylation by competitively inhibiting the binding of CHK2 to p53. Consequently, the expression of CDKN1A is decreased and that of SLC7A11 is increased, leading to the inhibition of apoptosis and ferroptosis. In contrast, phosphor‐deficient RFNG S225A mutant showed increased apoptosis and ferroptosis, and exhibited a notable response to oxaliplatin chemotherapy both in vitro and in vivo. It is further revealed that patients with low RFNG pS255 exhibited significant sensitivity to oxaliplatin in a patient‐derived xenograft (PDX) model. These findings highlight the crosstalk between the MAPK and p53 signaling pathways through RFNG, which mediates oxaliplatin resistance in CRC. Additionally, this study provides guidance for oxaliplatin treatment of CRC patients. |
| format | Article |
| id | doaj-art-564ea172443e45f88d345e0f7a65aa7a |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Wiley |
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| series | Advanced Science |
| spelling | doaj-art-564ea172443e45f88d345e0f7a65aa7a2025-08-20T02:17:06ZengWileyAdvanced Science2198-38442024-10-011138n/an/a10.1002/advs.202402795MAPK Signaling‐Mediated RFNG Phosphorylation and Nuclear Translocation Restrain Oxaliplatin‐Induced Apoptosis and FerroptosisYuqin Di0Xiang Zhang1Xiangqiong Wen2Jiale Qin3Lvlan Ye4Youpeng Wang5Mei Song6Ziyang Wang7Weiling He8Molecular Diagnosis and Gene Testing Center The First Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510080 ChinaDepartment of Gastrointestinal Surgery The First Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510080 ChinaDepartment of Gastrointestinal Surgery The First Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510080 ChinaDepartment of Gastrointestinal Surgery The First Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510080 ChinaDepartment of Gastrointestinal Surgery The First Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510080 ChinaCenter of Hepato‐Pancreato‐Biliary Surgery The First Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510080 ChinaInstitute of Precision Medicine The First Affiliated Hospital Sun Yat‐Sen University Guangzhou Guangdong 510080 ChinaDepartment of Gastrointestinal Surgery The First Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510080 ChinaDepartment of Gastrointestinal Surgery The First Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510080 ChinaAbstract Chemotherapy resistance remains a major challenge in the treatment of colorectal cancer (CRC). Therefore, it is crucial to develop novel strategies to sensitize cancer cells to chemotherapy. Here, the fringe family is screened to determine their contribution to chemotherapy resistance in CRC. It is found that RFNG depletion significantly sensitizes cancer cells to oxaliplatin treatment. Mechanistically, chemotherapy‐activated MAPK signaling induces ERK to phosphorylate RFNG Ser255 residue. Phosphorylated RFNG S255 (pS255) interacts with the nuclear importin proteins KPNA1/importin‐α1 and KPNB1/importin‐β1, leading to its translocation into the nucleus where it targets p53 and inhibits its phosphorylation by competitively inhibiting the binding of CHK2 to p53. Consequently, the expression of CDKN1A is decreased and that of SLC7A11 is increased, leading to the inhibition of apoptosis and ferroptosis. In contrast, phosphor‐deficient RFNG S225A mutant showed increased apoptosis and ferroptosis, and exhibited a notable response to oxaliplatin chemotherapy both in vitro and in vivo. It is further revealed that patients with low RFNG pS255 exhibited significant sensitivity to oxaliplatin in a patient‐derived xenograft (PDX) model. These findings highlight the crosstalk between the MAPK and p53 signaling pathways through RFNG, which mediates oxaliplatin resistance in CRC. Additionally, this study provides guidance for oxaliplatin treatment of CRC patients.https://doi.org/10.1002/advs.202402795apoptosis and ferroptosisMAPK signalingnuclear RFNGoxaliplatin chemosensitivityp53 activity |
| spellingShingle | Yuqin Di Xiang Zhang Xiangqiong Wen Jiale Qin Lvlan Ye Youpeng Wang Mei Song Ziyang Wang Weiling He MAPK Signaling‐Mediated RFNG Phosphorylation and Nuclear Translocation Restrain Oxaliplatin‐Induced Apoptosis and Ferroptosis Advanced Science apoptosis and ferroptosis MAPK signaling nuclear RFNG oxaliplatin chemosensitivity p53 activity |
| title | MAPK Signaling‐Mediated RFNG Phosphorylation and Nuclear Translocation Restrain Oxaliplatin‐Induced Apoptosis and Ferroptosis |
| title_full | MAPK Signaling‐Mediated RFNG Phosphorylation and Nuclear Translocation Restrain Oxaliplatin‐Induced Apoptosis and Ferroptosis |
| title_fullStr | MAPK Signaling‐Mediated RFNG Phosphorylation and Nuclear Translocation Restrain Oxaliplatin‐Induced Apoptosis and Ferroptosis |
| title_full_unstemmed | MAPK Signaling‐Mediated RFNG Phosphorylation and Nuclear Translocation Restrain Oxaliplatin‐Induced Apoptosis and Ferroptosis |
| title_short | MAPK Signaling‐Mediated RFNG Phosphorylation and Nuclear Translocation Restrain Oxaliplatin‐Induced Apoptosis and Ferroptosis |
| title_sort | mapk signaling mediated rfng phosphorylation and nuclear translocation restrain oxaliplatin induced apoptosis and ferroptosis |
| topic | apoptosis and ferroptosis MAPK signaling nuclear RFNG oxaliplatin chemosensitivity p53 activity |
| url | https://doi.org/10.1002/advs.202402795 |
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