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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-1? 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-1? 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-1? 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-1? and aerobic glycolysis is a protective response to the metabolic stress generated by IMQ treatment, and thus, co-treatment with inhibitors of HIF-1? and/or glycolysis may be a useful therapeutic strategy to enhance the anti-tumor effects of IMQ in clinical settings.

SUBMITTER: Huang SW 

PROVIDER: S-EPMC4012728 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Targeting aerobic glycolysis and HIF-1alpha expression enhance imiquimod-induced apoptosis in cancer cells.

Huang Shi-Wei SW   Kao Jun-Kai JK   Wu Chun-Ying CY   Wang Sin-Ting ST   Lee Hsin-Chen HC   Liang Shu-Mei SM   Chen Yi-Ju YJ   Shieh Jeng-Jer JJ  

Oncotarget 20140301 5


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  ...[more]

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