Trichothecin Inhibits Cancer-Related Features in Colorectal Cancer Development by Targeting STAT3

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.

Targeting lipid metabolism with natural products: A novel strategy for gastrointestinal cancer therapy

“…Trichothecin (TCN) is a sesquiterpenoid found in an endophytic fungus on the herbal plant, Maytenus hookeri Loes. TCN has a strong inhibitory effect on the invasion and metastasis of colon cancer cells (Qi et al, 2020), and mechanistically, it reduces the production of unsaturated FAs by blocking SCD‐1 activity. The transcriptional activity of the SCD‐1 promoter decreases significantly after TCN treatment, and the transcription factor, SREBP1, participates in the downregulation of SCD‐1 through TCN treatment (Liao et al, 2020).…”

The complementary roles of STAT3 and STAT1 in cancer biology: insights into tumor pathogenesis and therapeutic strategies

“…Thus, therapeutic approaches that specifically downregulate STAT3 transcriptional activity and/ or upregulate STAT1 transcriptional activity may be promising in cancer treatment (86) (Tables 6, 7). One such example is trichothecin, a novel STAT3 inhibitor that was found to inhibit STAT3 activation and dimerization, but not affect phosphorylation levels of STAT1 (88). Tissue transglutaminase, an enzyme that crosslinks proteins between an ϵ-amino group of a lysine residue and a g-carboxamide group of glutamine residue, is overexpressed in many cancer cells.…”