Oncotarget

Research Papers:

Targeting Aerobic Glycolysis and HIF-1α Expression Enhance Imiquimod-induced Apoptosis in Cancer Cells

Shi-Wei Huang, Jun-Kai Kao, Chun-Ying Wu, Sin-Ting Wang, Hsin-Chen Lee, Shu-Mei Liang, Yi-Ju Chen and Jeng-Jer Shieh _

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Oncotarget. 2014; 5:1363-1381. https://doi.org/10.18632/oncotarget.1734

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Abstract

Shi-Wei Huang1, Jun-Kai Kao1,2, Chun-Ying Wu3, Sin-Ting Wang1,3, Hsin-Chen Lee4, Shu-Mei Liang5, Yi-Ju Chen6, Jeng-Jer Shieh1,7,8

1Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan

2Department of Pediatrics, Children's Hospital, Changhua Christian Hospital, Changhua, Taiwan

3Division of Gastroenterology and Hepatology, Taichung Veterans General Hospital, Taichung, Taiwan

4Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan

5Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan

6Department of Dermatology, Taichung Veterans General Hospital, Taichung, Taiwan

7Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan

8Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan

Correspondence:

Dr. Jeng-Jer Shieh, e-mail: shiehjj@vghtc.gov.tw

Short title: Aerobic glycolysis and HIF-1α in imiquimod-induced apoptosis

Keywords: imiquimod, aerobic glycolysis, HIF-1α, apoptosis

Received: December 31, 2013     Accepted: March 08, 2014      Published: March 12, 2014

ABSTRACT:

Tumor cells rely on aerobic glycolysis to maintain unconstrained cell growth and proliferation. Imiquimod (IMQ), a synthetic Toll-like receptor (TLR) 7/8 ligand, exerts anti-tumor effects directly by inducing cell death in cancer cells and/or indirectly by activating cellular immune responses against tumor cells. However, whether IMQ modulates glucose metabolism pathways remains unclear. In this study, we demonstrated that IMQ can enhance aerobic glycolysis by up-regulating HIF-1α expression at the transcriptional and translational levels via ROS mediated STAT3- and Akt-dependent pathways, independent of TLR7/8 signaling. The genetic silencing of HIF-1α not only repressed IMQ-induced aerobic glycolysis but also sensitized cells to IMQ-induced apoptosis due to faster ATP and Mcl-1 depletion. Moreover, the glucose analog 2-DG and the Hsp90 inhibitor 17-AAG, which destabilizes the HIF-1α protein, synergized with IMQ to induce tumor cell apoptosis in vitro and significantly inhibited tumor growth in vivo. Thus, we hypothesize that the IMQ-induced up-regulation of HIF-1α and aerobic glycolysis is a protective response to the metabolic stress generated by IMQ treatment, and thus, co-treatment with inhibitors of HIF-1α and/or glycolysis may be a useful therapeutic strategy to enhance the anti-tumor effects of IMQ in clinical settings.


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