Abstract
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that contributes to cancer progression through multiple processes of cancer development, which makes it an attractive target for cancer therapy. The IL-6/STAT3 pathway is associated with an advanced stage in colorectal cancer patients. In this study, we identified trichothecin (TCN) as a novel STAT3 inhibitor. TCN was found to bind to the SH2 domain of STAT3 and inhibit STAT3 activation and dimerization, thereby blocking STAT3 nuclear translocation and transcriptional activity. TCN did not affect phosphorylation levels of STAT1. TCN significantly inhibited cell growth, arrested cell cycle at the G0/G1 phase, and induced apoptosis in HCT 116 cells. In addition, the capacities of colony formation, migration, and invasion of HCT 116 cells were impaired upon exposure to TCN with or without IL-6 stimulation. In addition, TCN treatment abolished the tube formation of HUVEC cells in vitro. Taken together, these results highlight that TCN inhibits various cancer-related features in colorectal cancer development in vitro by targeting STAT3, indicating that TCN is a promising STAT3 inhibitor that deserves further exploration in the future.
Highlights
Signal transducers and activators of transcription 3 (STAT3) is an important member of the family of signal transducers and activators of transcription, which participates in relaying signals from cytokines and growth factors [1]
We demonstrate that TCN treatment inhibits the phosphorylation of Signal transducer and activator of transcription 3 (STAT3) by directly binding to its Src homologous region 2 (SH2) domain, resulting in inhibition of dimerization, nuclear translocation, and transcriptional activity of STAT3, thereby inhibiting multiple cancer-related features in colorectal cancer development in vitro
These results indicate that TCN is able to promote cell apoptosis in colorectal cancer HCT
Summary
Signal transducers and activators of transcription 3 (STAT3) is an important member of the family of signal transducers and activators of transcription, which participates in relaying signals from cytokines and growth factors [1]. STAT3 consists of 770 amino acids that constitute six different functional domains, including an amino-terminal domain (NTD), coiled-coil domain (CCD), DNA-binding domain (DBD), linker domain, SH2 domain, and the carboxyl-terminal transactivation domain (TAD) [2]. Chronic inflammation is regarded as an important risk factor for the development of colorectal cancer, and IL-6/STAT3 activation seems to take a center stage in human cancer development [10,11]. The abnormal activation of STAT3 upregulates its Molecules 2020, 25, 2306; doi:10.3390/molecules25102306 www.mdpi.com/journal/molecules
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