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Int J Biol Sci 2019; 15(4):826-837. doi:10.7150/ijbs.31749 This issue Cite

Research Paper

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

Li Zhou^1*✉, Ming Li^3,4*, Xinyou Yu², Feng Gao^5✉, Wei Li^6✉

1. Department of Pathology, Xiangya Hospital of Central South University, Changsha, Hunan 410008, P.R. China
2. Shandong Lvdu Bio-Industry Co., Ltd., Binzhou, Shandong 256600, P.R. China
3. School of Stomatology, Hunan University of Chinese Medicine, Changsha, Hunan 410208, P.R. China
4. Changsha Stomatological Hospital, Changsha, Hunan 410004, P.R. China.
5. Department of Ultrasonography, The Third Xiangya Hospital of Central South University, Changsha, Hunan, 410013, P.R. China
6. Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
* These authors contributed equally to this work.

✉ Corresponding authors: Li Zhou, Department of Pathology, Xiangya Hospital of Central South University, Changsha, Hunan 410008, P.R. China. E-mail: zhouli_723com or Feng Gao, Address: Department of Ultrasonography, The Third Xiangya Hospital of Central South University, Changsha, Hunan, 410013, P.R. China. E-mail: gf0731edu.cn or Wei Li, Address: Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China. E-mail: weililxedu.cn More

Abstract

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 in vivo 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.

Keywords: non-small cell lung cancer, piperlongumine, glycolysis, Hexokinases II, Akt

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