Novel insights into skyrin action in cancer cells.

Skyrin (SKR) is a bisanthraquinone secondary metabolite found in various fungi and plant species. Although it has demonstrated anticancer potential, its mechanism of action remains largely unclear. In this study, we investigated the biological effects of SKR in multiple cancer cell lines to further understand its molecular activity. We first examined the mechanism of previously reported SKR-induced upregulation of death receptor 5 (DR5) in HCT 116 and HT-29 colorectal cancer cells. Western blot analysis and siRNA experiments revealed that this upregulation was independent of the tumor suppressor protein p53 and instead implicated endoplasmic reticulum stress-inducible transcription factor CHOP. We next investigated whether SKR can induce reactive oxygen species formation. However, flow cytometry analysis demonstrated, for the first time, that SKR exhibited antioxidant activity in live cells. Finally, we explored the potential interaction between SKR and breast cancer-resistance protein (BCRP) using the HL-60 leukemic cell line with low BCRP expression and its BCRP-overexpressing subclone (cBCRP). Inhibition of BCRP led to increased intracellular accumulation of SKR in cBCRP cells, suggesting that SKR is a novel BCRP substrate. Furthermore, BCRP inhibition sensitized these cells to SKR treatment, as reflected by decreased metabolic activity and a reduced total number of cells. In conclusion, our findings provide new mechanistic insight into the anticancer effects of SKR. These results support the potential application of SKR in cancer prevention and therapy, particularly in tumors with dysfunctional p53.