Heliyon (Aug 2023)
Brevilin A exerts anti-colorectal cancer effects and potently inhibits STAT3 signaling in vitro
Abstract
Colorectal cancer (CRC) is the third most common cause of cancer-related morbidity worldwide, with an estimated of 1.85 million new cases and 850,000 deaths every year. Nevertheless, the current treatment regimens for CRC have many disadvantages, including toxicities and off-targeted side effects. STAT3 (signal transducer and activator of transcription 3) has been considered as a promising molecular target for CRC therapy. Brevilin A, a sesquiterpene lactone compound rich in Centipedae Herba has potent anticancer effects in nasopharyngeal, prostate and breast cancer cells by inhibiting the STAT3 signaling. However, the anti-CRC effect of brevilin A and the underlying mechanism of action have not been fully elucidated. In this study, we aimed to investigate the involvement of STAT3 signaling in the anti-CRC action of brevilin A. Here, HCT-116 and CT26 cell models were used to investigate the anti-CRC effects of brevilin A in vitro. HCT-116 cells overespressing with STAT3 were used to evaluate the involvement of STAT3 signaling in the anti-CRC effect of brevilin A. Screening of 49 phosphorylated tyrosine kinases in the HCT-116 cells after brevilin A treatment was performed by using the human phospho-receptor tyrosine kinase (phospho-RTK) array. Results showed that brevilin A inhibited cell proliferation and cell viability, induced apoptosis, reduced cell migration and invasion, inhibited angiogenesis, lowered the protein expression levels of phospho-Src (Tyr416), phospho-JAK2 (Y1007/1008) and phospho-STAT3 (Tyr705), and inhibited STAT3 activation and nuclear localization. Brevilin A also significantly reduced the protein expression levels of STAT3 target genes, such as MMP-2, VEGF and Bcl-xL. More importantly, over-activation of STAT3 diminished brevilin A's effects on cell viability. All these results suggest that brevilin A exerts potent anti-CRC effects, at least in part, by inhibiting STAT3 signaling. Our findings provide a strong pharmacological basis for the future exploration and development of brevilin A as a novel STAT3-targeting phytotherapeutic agent for CRC treatment.
