Sinomenine Inhibits Non-Small Cell Lung Cancer via Downregulation of Hexokinases II-Mediated Aerobic Glycolysis

OncoTargets and Therapy

关键词: sinomenine;    non-small cell lung cancer;    glycolysis;    hexokinase 2;   

DOI  :  

来源: DOAJ

【 摘 要 】

Wenbin Liu,1,* Xinfang Yu,2,* Li Zhou,3,* Jigang Li,1 Ming Li,4,5 Wei Li,6 Feng Gao7 1Department of Pathology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410006, People’s Republic of China; 2Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA; 3Department of Pathology, Xiangya Hospital of Central South University, Changsha, Hunan 410008, People’s Republic of China; 4School of Stomatology, Hunan University of Chinese Medicine, Changsha, Hunan 410208, People’s Republic of China; 5Changsha Stomatological Hospital, Hunan University of Chinese Medicine, Changsha, Hunan, 410004, People’s Republic of China; 6Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, People’s Republic of China; 7Department of Ultrasonography, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei Li; Feng Gao Email [e-mail]; [e-mail]: Addiction to aerobic glycolysis is a common metabolic phenotype in human non-small cell lung cancer (NSCLC). The natural product Sinomenine (Sin) exhibits significant anti-tumor effects in various human cancers. However, the underlying mechanism remains elusive.Methods: The inhibitory effect of Sin on NSCLC cells was determined by MTS and soft agar assays. The glycolysis efficacy of NSCLC cells was examined by glucose uptake and lactate production. The activation of Akt signaling and the protein level of hexokinases II (HK2) were examined by immunoblot (IB), qRT-PCR, and immunohistochemical staining (IHC). The in vivo anti-tumor effect of Sin was validated by the xenograft mouse model.Results: We showed that HK2 is highly expressed in NSCLC tissues and cell lines. Depletion of HK2 suppressed cell viability, anchorage-independent colony formation, and xenograft tumor growth. Sinomenine exhibited a profound inhibitory effect on NSCLC cells by reducing HK2-mediated glycolysis both in vitro and in vivo. Ectopic overexpression of HK2 compromised these anti-tumor efficacies in sinomenine-treated NSCLC cells. Moreover, we revealed that sinomenine decreased Akt activity, which caused the down-regulation of HK2-mediated glycolysis. Knockdown of Akt reduced HK2 protein level and impaired glycolysis. In contrast, overexpression of constitutively activated Akt1 reversed this phenotype.Conclusion: This study suggests that targeting HK2-mediated aerobic glycolysis is required for sinomenine-mediated anti-tumor activity.Keywords: sinomenine, non-small cell lung cancer, glycolysis, hexokinase 2

【 授权许可】

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