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ALK fusion promotes metabolic reprogramming of cancer cells by transcriptionally upregulating PFKFB3.
Hu, Mengnan; Bao, Ruoxuan; Lin, Miao; Han, Xiao-Ran; Ai, Ying-Jie; Gao, Yun; Guan, Kun-Liang; Xiong, Yue; Yuan, Hai-Xin.
Afiliación
  • Hu M; The Fifth People's Hospital of Shanghai and the Molecular and Cell Biology Laboratory of the Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
  • Bao R; The Fifth People's Hospital of Shanghai and the Molecular and Cell Biology Laboratory of the Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
  • Lin M; Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
  • Han XR; Department of Thoracic Surgery, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China.
  • Ai YJ; Cullgen (Shanghai) Inc., 230 Chuan Hong Road, Pu Dong New Area, Shanghai, China.
  • Gao Y; Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China.
  • Guan KL; The Fifth People's Hospital of Shanghai and the Molecular and Cell Biology Laboratory of the Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
  • Xiong Y; Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, 92093, USA.
  • Yuan HX; Cullgen Inc., 12671 High Bluff Drive, San Diego, CA, 92130, USA.
Oncogene ; 41(40): 4547-4559, 2022 09.
Article en En | MEDLINE | ID: mdl-36064579
ABSTRACT
Anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase of the insulin receptor kinase subfamily, is activated in multiple cancer types through translocation or overexpression. Although several generations of ALK tyrosine kinase inhibitors (TKIs) have been developed for clinic use, drug resistance remains a major challenge. In this study, by quantitative proteomic approach, we identified the glycolytic regulatory enzyme, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), as a new target of ALK. Expression of PFKFB3 is highly dependent on ALK activity in ALK+ anaplastic large cell lymphoma and non-small-cell lung cancer (NSCLC) cells. Notably, ALK and PFKFB3 expressions exhibit significant correlation in clinic ALK+ NSCLC samples. We further demonstrated that ALK promotes PFKFB3 transcription through the downstream transcription factor STAT3. Upregulation of PFKFB3 by ALK is important for high glycolysis level as well as oncogenic activity of ALK+ lymphoma cells. Finally, targeting PFKFB3 by its inhibitor can overcome drug resistance in cells bearing TKI-resistant mutants of ALK. Collectively, our studies reveal a novel ALK-STAT3-PFKFB3 axis to promote cell proliferation and tumorigenesis, providing an alternative strategy for the treatment of ALK-positive tumors.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma de Pulmón de Células no Pequeñas / Neoplasias Pulmonares Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2022 Tipo del documento: Article País de afiliación: China

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma de Pulmón de Células no Pequeñas / Neoplasias Pulmonares Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2022 Tipo del documento: Article País de afiliación: China
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