The presence of key hypoxia regulators, namely, hypoxia-inducible factor (HIF)-1α or HIF-2α, in tumors is associated with poor patient prognosis. Hypoxia massively activates several genes, including the one encoding the BCRP transporter that proffers multidrug resistance to cancer cells through the xenobiotic efflux and is a determinant of the side population (SP) associated with cancer stem-like phenotypes. As natural medicine comes to the fore, it is instinctive to look for natural agents possessing powerful features against cancer resistance. Hypericin, a pleiotropic agent found in Hypericum plants, is a good example as it is a BCRP substrate and potential inhibitor, and an SP and HIF modulator. Here, we showed that hypericin efficiently accumulated in hypoxic cancer cells, degraded HIF-1/2α, and decreased BCRP efflux together with hypoxia, thus diminishing the SP population. On the contrary, this seemingly favorable result was accompanied by the stimulated migration of this minor population that preserved the SP phenotype. Because hypoxia unexpectedly decreased the BCRP level and SP fraction, we compared the SP and non-SP proteomes and their changes under hypoxia in the A549 cell line. We identified differences among protein groups connected to the epithelial-mesenchymal transition, although major changes were related to hypoxia, as the upregulation of many proteins, including serpin E1, PLOD2 and LOXL2, that ultimately contribute to the initiation of the metastatic cascade was detected. Altogether, this study helps in clarifying the innate and hypoxia-triggered resistance of cancer cells and highlights the ambivalent role of natural agents in the biology of these cells.
- Klíčová slova
- Breast cancer resistance protein, ECM reorganization, Hypericin, Hypoxia, Proteomics, Side population,
- MeSH
- ABC transportér z rodiny G, člen 2 genetika metabolismus MeSH
- faktor 1 indukovatelný hypoxií - podjednotka alfa metabolismus MeSH
- hypoxie buňky MeSH
- hypoxie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádorové proteiny genetika metabolismus MeSH
- nádory * metabolismus MeSH
- regulace genové exprese u nádorů MeSH
- transkripční faktory bHLH genetika metabolismus MeSH
- vedlejší populace buněk * patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- ABC transportér z rodiny G, člen 2 MeSH
- faktor 1 indukovatelný hypoxií - podjednotka alfa MeSH
- hypericin MeSH Prohlížeč
- nádorové proteiny MeSH
- transkripční faktory bHLH MeSH
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.
- Klíčová slova
- Death receptor 5, Hypericum, TRAIL, TRAIL resistance, colorectal cancer, hypoxia, proteomics, skyrin,
- Publikační typ
- časopisecké články MeSH
