Semilicoisoflavone B induces oral cancer cell apoptosis by targeting claspin and ATR‐Chk1 signaling pathways

Abstract

AbstractThe prevalence of oral squamous cell carcinoma (OSCC) is increasing worldwide mainly due to poor oral hygiene and unrestricted lifestyle. Advanced‐stage OSCC is associated with poor prognosis and a 5‐year survival rate of only 30%–50%. The present study was designed to investigate the anticancer effect and mode of action of Glycyrrhiza‐derived semilicoisoflavone B (SFB) in 5‐fluorourasil (5FU)‐resistant human OSCC cell lines. The study findings revealed that SFB significantly reduces OSCC cell viability and colony formation ability by arresting cell cycle at the G2/M and S phases and reducing the expressions of key cell cycle regulators including cyclin A, cyclin B, CDC2, and CDK2. The compound caused a significant induction in the percentage of nuclear condensation and apoptotic cells in OSCC. Regarding pro‐apoptotic mode of action, SFB was found to increase Fas‐associated death domain and death receptor 5 expressions and reduce decoy receptor 2 expression, indicating involvement of extrinsic pathway. Moreover, SFB was found to increase pro‐apoptotic Bim expression and reduce anti‐apoptotic Bcl‐2 and Bcl‐xL expressions, indicating involvement of intrinsic pathway. Moreover, SFB‐mediated induction in cleaved caspases 3, 8, and 9 and cleaved poly(ADP‐ribose) polymerase confirmed the induction of caspase‐mediated apoptotic pathways. Regarding upstream signaling pathway, SFB was found to reduce extracellular signal regulated kinase 1/2 (ERK) phosphorylation to execute its pro‐apoptotic activity. The Human Apoptotic Array findings revealed that SFB suppresses claspin expression, which in turn caused reduced phosphorylation of ATR, checkpoint kinase 1 (Chk1), Wee1, and CDC25C, indicating disruption of ATR‐Chk1 signaling pathway by SFB. Taken together, these findings indicate that SFB acts as a potent anticancer compound against 5FU‐resistant OSCC by modulating mitogen‐activated protein kinase (MAPK) and ATR‐Chk1 signaling pathways.