title: Targeting aerobic glycolysis and HIF-1alpha expression enhance imiquimod-induced apoptosis in cancer cells.
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.
authors.affiliation: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Shi-Wei
authors.initials: SW
authors.lastname: Huang
authors.forename: Jun-Kai
authors.initials: JK
authors.lastname: Kao
authors.forename: Chun-Ying
authors.initials: CY
authors.lastname: Wu
authors.forename: Sin-Ting
authors.initials: ST
authors.lastname: Wang
authors.forename: Hsin-Chen
authors.initials: HC
authors.lastname: Lee
authors.forename: Shu-Mei
authors.initials: SM
authors.lastname: Liang
authors.forename: Yi-Ju
authors.initials: YJ
authors.lastname: Chen
authors.forename: Jeng-Jer
authors.initials: JJ
authors.lastname: Shieh
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003847:Deoxyglucose / Q000494:pharmacology / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005786:Gene Expression Regulation / Q000187:drug effects*; D020868:Gene Silencing; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D000077271:Imiquimod; D015603:Keratinocytes; D047029:Lactams, Macrocyclic / Q000494:pharmacology / Q000627:therapeutic use; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D014176:Protein Biosynthesis / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051199:Toll-Like Receptor 7 / Q000235:genetics; D051200:Toll-Like Receptor 8 / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000634:Aminoquinolines; D000970:Antineoplastic Agents; D016227:Benzoquinones; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047029:Lactams, Macrocyclic; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; C112765:tanespimycin; D003847:Deoxyglucose; D051057:Proto-Oncogene Proteins c-akt; D000077271:Imiquimod