Abstract
Signal transducer and activator of transcription 3 (STAT3) plays a critical role in the formation and growth of human cancer. Therefore, STAT3 is a therapeutic target for cancer drug discovery. Acacetin, a flavone present in various plants, inhibits constitutive and inducible STAT3 activation in STAT3-activated DU145 prostate cancer cells. Acacetin inhibits STAT3 activity by directly binding to STAT3, which we confirmed by a pull-down assay with a biotinylated compound and two level-free methods, namely, a drug affinity responsive target stability (DARTS) experiment and a cellular thermal shift assay (CETSA). Acacetin inhibits STAT3 phosphorylation at the tyrosine 705 residue and nuclear translocation in DU145 cells, which leads to the downregulation of STAT3 target genes. Acacetin then induces apoptosis in a time-dependent manner. Interestingly, acacetin induces the production of reactive oxygen species (ROS) that are not involved in the acacetin-induced inhibition of STAT3 activation because the suppressed p-STAT3 level is not rescued by treatment with GSH or NAC, which are general ROS inhibitors. We also found that acacetin inhibits tumor growth in xenografted nude mice. These results suggest that acacetin, as a STAT3 inhibitor, could be a possible drug candidate for targeting STAT3 for the treatment of cancer in humans.
Highlights
Cancer is a leading cause of death worldwide and its incidence is increasing continuously [1]
We identified acacetin as a Signal transducer and activator of transcription 3 (STAT3) inhibitor and verified that acacetin directly binds to STAT3 using various biochemical methods, including a pull-down assay, a drug affinity responsive target stability (DARTS) experiment, and a cellular thermal shift assay (CETSA), in DU145 prostate cancer cells with constitutively active STAT3 [18,19]
STAT3 is constitutively activated in DU145 cells and the cells were used to validate the fact that STAT3 inhibitors regulate the phosphorylation of
Summary
Cancer is a leading cause of death worldwide and its incidence is increasing continuously [1]. STAT3 is constitutively activated in many different types of cancers and tumor-infiltrating immune cells and has been associated with a poor prognosis [3,4]. Elevated levels of IL-6 are observed in a large number of patients with solid tumors including prostate cancer, and IL6 stimulates the activation of STAT3 signaling pathway, which is often associated with poor patient outcomes [2]. We identified acacetin as a STAT3 inhibitor and verified that acacetin directly binds to STAT3 using various biochemical methods, including a pull-down assay, a drug affinity responsive target stability (DARTS) experiment, and a cellular thermal shift assay (CETSA), in DU145 prostate cancer cells with constitutively active STAT3 [18,19]. Acacetin showed antitumor activity in STAT3-activated DU145 cells via STAT3 inhibition and ROS generation
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