Sugiol inhibits STAT3 activity via regulation of transketolase and ROS-mediated ERK activation in DU145 prostate carcinoma cells

Abstract

Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in various human cancers and has been used as a therapeutic target for tumors. This study screened natural products to identify compounds that inhibit STAT3 activity using a STAT3-dependent luciferase reporter system. Sugiol was identified as a compound that decreased luciferase activity in a dose-dependent manner. Sugiol specifically inhibited STAT3 phosphorylation at Tyr-705 in DU145 prostate cells, and this inhibition was independent of the STAT3 upstream kinase. Sugiol induced cell cycle arrest and decreased the expression levels of STAT3 target genes, such as cyclin D1, cyclin A, and survivin. Notably, we observed that sugiol interacted with transketolase, an enzyme in central metabolism, and increased ROS levels leading to the activation of ERK, which inhibits STAT3 activity. The protein phosphatase MEG2 was also responsible for sugiol-induced STAT3 dephosphorylation. The inhibitory effect of sugiol on cell growth was confirmed using the DU145 mouse xenograft model. We propose that sugiol inhibits STAT3 activity through a mechanism that involves the inhibition of transketolase, which leads to increased ROS levels and MEG2 activation in DU145 cells. Therefore, sugiol is the first compound regulating STAT3 activity via modulation of cancer metabolic pathway and we suggest the use of sugiol as an inhibitor of the STAT3 pathway for the treatment of human solid tumors with activated STAT3.