Death Receptor 5 (TNFRSF10B) Is Upregulated and TRAIL Resistance Is Reversed in Hypoxia and Normoxia in Colorectal Cancer Cell Lines after Treatment with Skyrin, the Active Metabolite of Hypericum spp.

Simple Summary Hypoxic conditions are common in solid tumors and are very often connected with the poor prognosis of cancer patients. The lack of oxygen often causes the failure of therapy due to multiple mechanisms increasing cancer survival. Skyrin (SKR) is a secondary plant metabolite from the genus Hypericum spp., with a potential anticancer effects but still unknown mechanism of action. Based on our comprehensive analysis of SKR action, SKR shows significant efficiency against cancer, but not healthy cells, induces apoptosis, and upregulates Death receptor 5 in cancer cells in normoxic, as well as hypoxic conditions. SKR reverses TRAIL resistance even in TRAIL-resistant cancer cell lines in hypoxia. To sum up, SKR can be possibly used as a natural antitumor drug per se or as an adjuvant to TRAIL treatment in hypoxic and therapy-resistant tumors. Skyrin (SKR) is a plant bisanthraquinone secondary metabolite from the Hypericum genus with potential use in anticancer therapy. However, its effect and mechanism of action are still unknown. The negative effect of SKR on HCT 116 and HT-29 cancer cell lines in hypoxic and normoxic conditions was observed. HCT 116 cells were more responsive to SKR treatment as demonstrated by decreased metabolic activity, cellularity and accumulation of cells in the G1 phase. Moreover, an increasing number of apoptotic cells was observed after treatment with SKR. Based on the LC-MS comparative proteomic data from hypoxia and normoxia (data are available via ProteomeXchange with the identifier PXD019995), SKR significantly upregulated Death receptor 5 (DR5), which was confirmed by real-time qualitative PCR (RT-qPCR). Furthermore, multiple changes in the Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-activated cascade were observed. Moreover, the reversion of TRAIL resistance was observed in HCT 116, HT-29 and SW620 cell lines, even in hypoxia, which was linked to the upregulation of DR5. In conclusion, our results propose the use of SKR as a prospective anticancer drug, particularly as an adjuvant to TRAIL-targeting treatment to reverse TRAIL resistance in hypoxia.

Automated summary

Hypoxic conditions in tumors often lead to poor prognosis in cancer patients. Skyrin (SKR), a plant metabolite, has shown significant efficacy against cancer cells, while sparing healthy cells, and can reverse TRAIL resistance in hypoxic conditions. This suggests SKR could be a potential anticancer drug, especially as an adjuvant to TRAIL treatment in hypoxic and therapy-resistant tumors.