期刊
CANCER SCIENCE
卷 110, 期 1, 页码 366-378出版社
WILEY
DOI: 10.1111/cas.13852
关键词
2-Hydroxycinnamaldehyde; anticancer; antioxidant; ROS; STAT3
类别
资金
- KRIBB Research Initiative Program
- Bio-Synergy Research Project [NRF-2012M3A9C4048777]
- Bio & Medical Technology Development Program of the National Research Foundation [2015M3A9B5030311, NRF-2017M3A9A8032417]
- Korean Government
- National Research Foundation of Korea [2017M3A9A8032417, 2015M3A9B5030311] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Inhibition of the signal transducer and activator of transcription 3 (STAT3) signaling pathway is a novel therapeutic strategy to treat human cancers with constitutively active STAT3. During the screening of natural products to find STAT3 inhibitors, we identified 2 '-hydroxycinnamaldehyde (HCA) as a STAT3 inhibitor, which was isolated from the stem bark of Cinnamomum cassia. In this study, we found that HCA inhibited constitutive and inducible STAT3 activation in STAT3-activated DU145 prostate cancer cells. HCA selectively inhibited the STAT3 activity by direct binding to STAT3, which was confirmed by biochemical methods, including a pull-down assay with biotin-conjugated HCA, a drug affinity responsive target stability (DARTS) experiment and a cellular thermal shift assay (CETSA). HCA inhibited STAT3 phosphorylation at the tyrosine 705 residue, dimer formation, and nuclear translocation in DU145 cells, which led to a downregulation of STAT3 target genes. The downregulation of cell cycle progression and antiapoptosis-related gene expression by HCA induced the accumulation of cells in the G0/G1 phase of the cell cycle and then induced apoptosis. We also found that reactive oxygen species (ROS) were involved in the HCA-induced inhibition of STAT3 activation and cell proliferation because the suppressed p-STAT3 level was rescued by glutathione or N-acetyl-L-cysteine treatment, which are general ROS inhibitors. These results suggest that HCA could be a potent anticancer agent targeting STAT3-activated tumor cells.
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