The isoxazole derivative of usnic acid induces an ER stress response in breast cancer cells that leads to paraptosis-like cell death
- Author:
- Pyrczak-Felczykowska A., Reekie T.A., Jąkalski M., Hać A., Malinowska M., Pawlik A., Ryś K., Guzow-Krzemińska B. & Herman-Antosiewicz A.
- Year:
- 2022
- Journal:
- International Journal of Molecular Science
- Pages:
- 23: 1802 [21 p.]
- Url:
- https://doi.org/10.3390/ijms23031802
Derivatives of usnic acid (UA), a secondary metabolite from lichens, were synthesized to
improve its anticancer activity and selectivity. Recently we reported the synthesis and activity of an
UA isoxazole derivative, named 2b, against cancer cells of different origins. Herein, the molecular
mechanisms underlying its activity and efficacy in vivo were tested. The viability of breast cancer
or normal cells has been tested using an MTT assay. Cell and organelle morphology was analyzed
using light, electron and fluorescence microscopy. Gene expression was evaluated by RNAseq and
protein levels were evaluated by Western blotting. In vivo anticancer activity was evaluated in a
mice xenograft model. We found that 2b induced massive vacuolization which originated from the
endoplasmic reticulum (ER). ER stress markers were upregulated both at the mRNA and protein
levels. ER stress was caused by the release of Ca2+ ions from the ER by IP3R channels which was
mediated, at least partly, by phospholipase C (PLC)-synthetized 1,4,5-inositol triphosphate (IP3).
ER stress led to cell death with features of apoptosis and paraptosis. When applied to nude mice
with xenografted breast cancer cells, 2b stopped tumour growth. In mice treated with 2b, vacuolization was observed in tumour cells, but not in other organs. This study shows that the antiproliferative activity of 2b relates to the induction of ER stress in cancer, not in healthy, cells and it leads
to breast cancer cell death in vitro and in vivo.
Keywords: usnic acid; anticancer activity; ER stress; IP3R; apoptosis; paraptosis.
- Id:
- 34138
- Submitter:
- zdenek
- Post_time:
- Saturday, 05 February 2022 19:44