Research Papers:

Metformin alleviates nickel-induced autophagy and apoptosis via inhibition of hexokinase-2, activating lipocalin-2, in human bronchial epithelial cells

Yu-Ting Kang, Wen-Cheng Hsu, Chih-Hsien Wu, I-Lun Hsin, Pei-Ru Wu, Kun-Tu Yeh _ and Jiunn-Liang Ko

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Oncotarget. 2017; 8:105536-105552. https://doi.org/10.18632/oncotarget.22317

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Yu-Ting Kang1,*, Wen-Cheng Hsu2,*, Chih-Hsien Wu1,3, I-Lun Hsin1,4, Pei-Ru Wu6, Kun-Tu Yeh5,7 and Jiunn-Liang Ko1,8

1Institute of Medicine, Chung-Shan Medical University, Taichung, Taiwan

2Department of Endocrinology and Metabolism, Tungs’ Taichung MetroHarbor Hospital, Taichung, Taiwan

3Basic Medical Education Center, Central Taiwan University of Science and Technology, Taichung, Taiwan

4Inflammation Research & Drug Development Center, Changhua Christian Hospital, Changhua, Taiwan

5Department of Surgical Pathology, Changhua Christian Hospital, Changhua, Taiwan

6Department of Pathology, Cheng Ching Hospital, Taichung, Taiwan

7School of Medicine, Chung Shan Medical University, Taichung, Taiwan

8Department of Medical Oncology and Chest Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan

*These authors have contributed equally to this work

Correspondence to:

Kun-Tu Yeh, email: [email protected]

Jiunn-Liang Ko, email: [email protected]

Keywords: nickel; autophagy; hexokinase 2; lipocalin 2; metformin

Received: April 14, 2017    Accepted: June 29, 2017    Published: November 06, 2017


Autophagy is an intracellular recycling and degradation process for regulating tumor progression, survival and drug resistance. Nickel compounds have been identified as human carcinogens. However, the role of nickel-induced autophagy in lung carcinogenesis has not yet been fully elucidated. In this study, we determined that hexokinase 2 (HK2), which phosphorylates glucose and regulates autophagy, is the key mediator in nickel-induced autophagy in lung bronchial epithelial cells. We attempted to investigate the effects of the antidiabetic drug metformin on HK2 expression and lung cancer chemoprevention. Our results showed that metformin decreases nickel-induced autophagy and activation of apoptosis through inhibition of HK2 gene, protein and activity. Furthermore, we demonstrated that lipocalin 2 (LCN2), which is released by neutrophils at sites of infection and inflammation is involved in HK2-driven autophagy pathway. Knockdown of endogenous HK2 and LCN2 by shRNA reduced nickel-elicited autophagy and apoptosis, illustrating that metabolic alteration and inflammatory action are important in nickel-elicited carcinogenesis. We also determined the association between nickel-induced autophagy and apoptosis. Inhibition of nickel-induced autophagy abolished apoptotic cell death in chloroquine-treated, shLC3 Beas-2B cells and Atg5−/− MFFs. From TGCA database and immunohistochemistry analysis, HK2 and LCN2 expression increased in lung squamous cell carcinoma and their related adjacent normal tissues. Taken together, our results demonstrated that metformin alleviates NiCl2-induced autophagy and apoptosis via HK2-driven LCN2 activation in human bronchial epithelial cells. This novel mechanism provides a strategy for targeting nickel-elicited lung cancer progression, as well as for preventing HK2 cumulative damage triggered by environmental carcinogens.

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