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PTEN deficiency facilitates gemcitabine efficacy in cancer by modulating the phosphorylation of PP2Ac and DCK.
Jiang, Tian-Yi; Cui, Xiao-Wen; Zeng, Tian-Mei; Pan, Yu-Fei; Lin, Yun-Kai; Feng, Xiao-Fan; Tan, Ye-Xiong; Yuan, Zhen-Gang; Dong, Li-Wei; Wang, Hong-Yang.
Afiliación
  • Jiang TY; International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Naval Medical University, Shanghai 200438, China.
  • Cui XW; National Center for Liver Cancer, the Naval Medical University, Shanghai 201805, China.
  • Zeng TM; National Center for Liver Cancer, the Naval Medical University, Shanghai 201805, China.
  • Pan YF; Department of Oncology, Eastern Hepatobiliary Surgery Hospital, the Naval Medical University, Shanghai 201805, China.
  • Lin YK; Department of Oncology, Eastern Hepatobiliary Surgery Hospital, the Naval Medical University, Shanghai 201805, China.
  • Feng XF; International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Naval Medical University, Shanghai 200438, China.
  • Tan YX; National Center for Liver Cancer, the Naval Medical University, Shanghai 201805, China.
  • Yuan ZG; International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Naval Medical University, Shanghai 200438, China.
  • Dong LW; National Center for Liver Cancer, the Naval Medical University, Shanghai 201805, China.
  • Wang HY; National Center for Liver Cancer, the Naval Medical University, Shanghai 201805, China.
Sci Transl Med ; 15(704): eadd7464, 2023 07 12.
Article en En | MEDLINE | ID: mdl-37437018
Gemcitabine is a nucleoside analog that has been successfully used in the treatment of multiple cancers. However, intrinsic or acquired resistance reduces the chemotherapeutic potential of gemcitabine. Here, we revealed a previously unappreciated mechanism by which phosphatase and tensin homolog (PTEN), one of the most frequently mutated genes in human cancers, dominates the decision-making process that is central to the regulation of gemcitabine efficacy in cholangiocarcinoma (CCA). By investigating a gemcitabine-treated CCA cohort, we found that PTEN deficiency was correlated with the improved efficacy of gemcitabine-based chemotherapy. Using cell-based drug sensitivity assays, cell line-derived xenograft, and patient-derived xenograft models, we further confirmed that PTEN deficiency or genetic-engineering down-regulation of PTEN facilitated gemcitabine efficacy both in vitro and in vivo. Mechanistically, PTEN directly binds to and dephosphorylates the C terminus of the catalytic subunit of protein phosphatase 2A (PP2Ac) to increase its enzymatic activity, which further dephosphorylates deoxycytidine kinase (DCK) at Ser74 to diminish gemcitabine efficacy. Therefore, PTEN deficiency and high phosphorylation of DCK predict a better response to gemcitabine-based chemotherapy in CCA. We speculate that the combination of PP2A inhibitor and gemcitabine in PTEN-positive tumors could avoid the resistance of gemcitabine, which would benefit a large population of patients with cancer receiving gemcitabine or other nucleoside analogs.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de los Conductos Biliares / Colangiocarcinoma Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2023 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de los Conductos Biliares / Colangiocarcinoma Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2023 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos