Targeting Aerobic Glycolysis and HIF-1α 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.

Imiquimod-induced AMPK activation causes translation attenuation and apoptosis but not autophagy

“…We previously demonstrated that IMQ dramatically depleted the intracellular ATP content in cancer cell lines [16], and consistently, IMQ treatment significantly decreased the ATP content in other tested cells ( Fig. 2A).…”

“…Additionally, the IMQinduced up-regulation of aerobic glycolysis is an adaptive response that protects cancer cells from IMQ-induced metabolic stress, particularly ATP depletion [16]. Thus, we hypothesized that IMQinduced metabolic stress not only activates AMPK but also induces AMPK-dependent apoptosis and/or autophagy.…”

“…Recently, we demonstrated that the IMQ-induced up-regulation of aerobic glycolysis is a protective response for adaptation to metabolic stresses, particularly ATP depletion, generated through IMQ treatment in cancer cells [16]. Thus, to overcome IMQ-induced energetic stress, activating catabolic pathways for ATP generation by activating AMPK is a reasonable strategy.…”

miR-122-5p Inhibits the Proliferation, Invasion and Growth of Bile Duct Carcinoma Cells by Targeting ALDOA

“…Knockdown of ALDOA in QBC939 and RBE cells attenuated the cell proliferation and induced a higher apoptosis rate. This changes could probably be attributed to the functions of ALDOA in regulating glycolysis, the epithelial-mesenchymal transition and the cell cycle, as high aerobic glycolysis activity was seen in cancer progression and this is related to the inhibition of apoptosis [20]. As demonstrated by one previous study, although oxygen was presented, cancer cells still required activate glycolysis to proliferate since glycolysis affords the majority of the materials required for large-scale cell proliferation [21].…”

Trial Watch—Immunostimulation with cytokines in cancer therapy

“…35,68 Rather, investigators and practitioners are focusing their efforts on the possibility to use recombinant cytokines (at low doses and locally) to boost the anticancer activity of other immunotherapeutic regimens, including checkpoint blockers, [69][70][71][72] adoptive cell transfer, 73-76 oncolytic virotherapy, [77][78][79][80][81] DNA-and peptide-based vaccines, [82][83][84][85][86][87] dendritic cell (DC)-based interventions, [88][89][90][91][92] as well as other immunostimulatory agents like Toll-like receptor (TLR) agonists. [93][94][95][96][97] Here, we discuss recent preclinical and clinical advances in the development of recombinant cytokines for use as immunological adjuvants in cancer patients.…”