Imiquimod induces STAT3-mediated autophagy via ROS production in cancer cells

Autophagy is a highly conserved cellular catabolic pathway for degradation and recycling intracellular components in response to nutrient starvation or environmental stresses. Signal transducers and activators of transcription 3 (STAT3), a homodimric transcription factor, could be activated by several stimulation and cytokines, and then induces numerous pro-inflammatory cytokines and growth factors. Imiquimod (IMQ), a Toll-like receptor (TLR) 7 and 8 ligand, contains antitumor and antiviral activity in vitro and in vivo. Studies had shown that IMQ induces autophagy and activates STAT3 in several types of cells. However, the mechanisms of IMQ-induced autophagy are not well understood. In this study, we found that IMQ markedly increased LC3-II conversion and EGFP-LC3 puncta formation in dose- and time-dependent manner. We observed IMQ induced autophagy is associated with up-regulated STAT3 phosphorylation and nucleus translocalization. Treatment of ROS scavenger dramatically decreased STAT3 phosphorylation and inhibited IMQ-induced autophagy. Consistently, pharmacological inhibition or overexpression of dominant-negative STAT3 reduced LC3-II expression and EGFP-LC3 puncta formation in IMQ-treated cells. Interestingly, genetic silence of STAT3 promoted EGFP-LC3 puncta formation and LC3-ll expression in IMQ-treated cells. Our findings demonstrated that IMQ induced ROS to stimulate STAT3 and STAT3 may play an important role in regulation of IMQ induced autophagy. We first figure out a novel target of IMQ induced-autophagy. We considered these findings might contribute useful information to basic and clinical research and application.