P0137 Imiquimod induces HIF-1α expression and aerobic glycolysis to protect imiquimod-induced apoptosis in cancer cells

Background Tumour cells increase glucose uptake and predominantly utilise glycolysis instead of mitochondrial respiration, even in the presence of abundant oxygen (aerobic glycolysis, the Warburg effect). HIF-1 α is a major determinant for aerobic glycolysis and cancer cell homeostasis under cytotoxic stress. Targeting HIF-1 α may be a specific strategy for chemotherapy. Methods and Findings In this study, we demonstrated imiquimod, a synthetic Toll-like receptor (TLR) 7/8 ligand which contains anti-tumour effects, can promote aerobic glycolysis that was not required for expression of TLR7 or TLR8. This effect depends on up-regulation of HIF-1 α expression at the transcriptional and translational levels via ROS mediated STAT3-dependent and Akt-dependent pathways. The genetic silencing of HIF-1 α not only repressed imiquimod-induced aerobic glycolysis but also sensitised imiquimod-induced apoptosis due to faster ATP and Mcl-1 depletion. Moreover, the glucose analogue 2-DG and the HIF-1 α inhibitor 17-AAG synergised with imiquimod to induce tumour cell apoptosis in vitro and significantly inhibited tumour growth in vivo. Interpretation We suggest that imiquimod-induced aerobic glycolysis and HIF-1 α expression is a protective effect in response to imiquimod treatment, and therefore, co-treatment with inhibitors of HIF-1 α and/or glycolysis may be a useful therapeutic strategy to enhance the anti-tumour effects of imiquimod in clinical settings.