Repression of Hexokinases II-Mediated Glycolysis Contributes to Piperlongumine-Induced Tumor Suppression in Non-Small Cell Lung Cancer Cells

• Published in: International journal of biological sciences 2019-01, Vol.15 (4), p.826-837
• Main Authors: Zhou, Li, Li, Ming, Yu, Xinyou, Gao, Feng, Li, Wei
• Format: Article
• Language: English
• Subjects: Activation; AKT protein; AKT1 protein; Anticancer properties; Antitumor activity; Apoptosis; Apoptosis - drug effects; Cancer; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Deregulation; Dioxolanes - metabolism; Flow Cytometry; Gene Expression Regulation, Neoplastic - drug effects; Glycolysis; Glycolysis - drug effects; Hexokinase; Humans; Immunoblotting; Immunohistochemistry; Immunoprecipitation; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Non-small cell lung carcinoma; Research Paper; Signal transduction; Signal Transduction - drug effects; Signaling; Survival; Tissues; Tumor suppression; Tumors; Xenografts; Xenotransplantation
• ISSN: 1449-2288; 1449-2288
• DOI: 10.7150/ijbs.31749

Deregulation of glycolysis is a common phenomenon in human non-small cell lung cancer (NSCLC). In the present study, we reported the natural compound, piperlongumine, has a profound anti-tumor effect on NSCLC via regulation of glycolysis. Piperlongumine suppressed the proliferation, colony formation and HK2-mediated glycolysis in NSCLC cells. We demonstrated that exposure to piperlongumine disrupted the interaction between HK2 and VDAC1, induced the activation of the intrinsic apoptosis signaling pathway. Moreover, our results revealed that piperlongumine down-regulated the Akt signaling, exogenous overexpression of constitutively activated Akt1 in HCC827 and H1975 cells significantly rescued piperlongumine-induced glycolysis suppression and apoptosis. The xenograft mouse model data demonstrated the pivotal role of suppression of Akt activation and HK2-mediated glycolysis in mediating the antitumor effects of piperlongumine. The expression of HK2 was higher in malignant NSCLC tissues than that of the paired adjacent tissues, and was positively correlated with poor survival time. Our results suggest that HK2 could be used as a potential predictor of survival and targeting HK2 appears to be a new approach for clinical NSCLC prevention or treatment.