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Fumarate inhibits PTEN to promote tumorigenesis and therapeutic resistance of type2 papillary renal cell carcinoma.
Ge, Xin; Li, Mengdie; Yin, Jianxing; Shi, Zhumei; Fu, Yao; Zhao, Ningwei; Chen, Hongshan; Meng, Longxiyu; Li, Xinjian; Hu, Zhibin; Zhao, Xiaozhi; Guo, Hongqian; Qian, Xu.
Afiliación
  • Ge X; Department of Nutrition and Food Hygiene, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical U
  • Li M; Department of Nutrition and Food Hygiene, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical U
  • Yin J; Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.
  • Shi Z; Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.
  • Fu Y; Department of Pathology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, China.
  • Zhao N; Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, China; China Exposomics Institute, Shanghai 201203, China.
  • Chen H; Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing
  • Meng L; Department of Urology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Institute of Urology, Nanjing University, Nanjing, Jiangsu 210008, China.
  • Li X; CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • Hu Z; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Dep
  • Zhao X; Department of Urology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Institute of Urology, Nanjing University, Nanjing, Jiangsu 210008, China. Electronic address: zhaoxz@nju.edu.cn.
  • Guo H; Department of Urology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Institute of Urology, Nanjing University, Nanjing, Jiangsu 210008, China. Electronic address: dr.ghq@nju.edu.cn.
  • Qian X; Department of Nutrition and Food Hygiene, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical U
Mol Cell ; 82(7): 1249-1260.e7, 2022 04 07.
Article en En | MEDLINE | ID: mdl-35216667
Fumarate is an oncometabolite. However, the mechanism underlying fumarate-exerted tumorigenesis remains unclear. Here, utilizing human type2 papillary renal cell carcinoma (PRCC2) as a model, we show that fumarate accumulates in cells deficient in fumarate hydratase (FH) and inhibits PTEN to activate PI3K/AKT signaling. Mechanistically, fumarate directly reacts with PTEN at cysteine 211 (C211) to form S-(2-succino)-cysteine. Succinated C211 occludes tethering of PTEN with the cellular membrane, thereby diminishing its inhibitory effect on the PI3K/AKT pathway. Functionally, re-expressing wild-type FH or PTEN C211S phenocopies an AKT inhibitor in suppressing tumor growth and sensitizing PRCC2 to sunitinib. Analysis of clinical specimens indicates that PTEN C211 succination levels are positively correlated with AKT activation in PRCC2. Collectively, these findings elucidate a non-metabolic, oncogenic role of fumarate in PRCC2 via direct post-translational modification of PTEN and further reveal potential stratification strategies for patients with FH loss by combinatorial AKTi and sunitinib therapy.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Carcinoma Papilar / Carcinoma de Células Renales / Fosfohidrolasa PTEN / Fumaratos / Neoplasias Renales Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Mol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2022 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Carcinoma Papilar / Carcinoma de Células Renales / Fosfohidrolasa PTEN / Fumaratos / Neoplasias Renales Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Mol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2022 Tipo del documento: Article