Open Access2′‐Hydroxycinnamaldehyde inhibits proliferation and induces apoptosis via signal transducer and activator of transcription 3 inactivation and reactive oxygen species generation
Author(s) -
Yoon Yae Jin,
Kim YoungHwan,
Lee YuJin,
Choi Jiyeon,
Kim CheolHee,
Han Dong Cho,
Kwon ByoungMog
Publication year - 2019
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13852
Subject(s) - stat3 , du145 , stat protein , reactive oxygen species , chemistry , cell cycle , apoptosis , cell growth , survivin , microbiology and biotechnology , biology , cancer research , signal transduction , cancer cell , biochemistry , cancer , genetics , lncap
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.