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MAPK Signaling-Mediated RFNG Phosphorylation and Nuclear Translocation Restrain Oxaliplatin-Induced Apoptosis and Ferroptosis.
Di, Yuqin; Zhang, Xiang; Wen, Xiangqiong; Qin, Jiale; Ye, Lvlan; Wang, Youpeng; Song, Mei; Wang, Ziyang; He, Weiling.
Afiliação
  • Di Y; Molecular Diagnosis and Gene Testing Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
  • Zhang X; Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
  • Wen X; Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
  • Qin J; Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
  • Ye L; Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
  • Wang Y; Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
  • Song M; Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
  • Wang Z; Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
  • He W; Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China.
Adv Sci (Weinh) ; 11(38): e2402795, 2024 Oct.
Article em En | MEDLINE | ID: mdl-39120977
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-ß1, 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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Colorretais / Apoptose / Oxaliplatina / Ferroptose Limite: Animals / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Colorretais / Apoptose / Oxaliplatina / Ferroptose Limite: Animals / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article