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[논문] Indirubin-3′-monoxime induces paraptosis in MDA-MB-231 breast cancer cells by transmitting Ca2+ from endoplasmic reticulum to mitochondria

Archives of Biochemistry and Biophysics

4.013

0003-9861

698

SCIE

Purpose: Indirubin-3′ -monoxime (I3M) induces cell death in many cancer cells; however, whether I3M regulates
paraptosis is unclear. The present study aimed to investigate I3M-induced paraptosis.
Methods: We treated various cancer cells with I3M, and measured vacuole formation (a paraptosis marker) and the regulating signaling pathway such as endoplasmic reticulum (ER) stress, reactive oxygen species, and proteasomal dysfunction.
Results: We found that I3M induced small vacuole formation in MDA-MB-231 breast cancer cells and transient knockdown of eIF2α and CHOP significantly downregulated vacuolation in the ER and mitochondria, as well as cell death in response to I3M, indicating that I3M-meditaed paraptosis was upregulated by ER stress. Moreover, I3M accumulated ubiquitinylated proteins via proteasome dysfunction, which stimulated ER stress-mediated Ca2+ release. A Ca2+ chelator significantly downregulated vacuolation in the ER and mitochondria as well as cell death, suggesting that Ca2+ was a key regulator in I3M-induced paraptosis. Our results also revealed that Ca2+ finally transited in mitochondria through mitochondrial Ca2+ uniporter (MCU), causing I3M-mediated paraptosis; however, the paraptosis was completely inhibited by, ruthenium red, an MCU inhibitor.
Conclusion: I3M induced proteasomal dysfunction-mediated ER stress and subsequently promoted Ca2+ release, which was accumulated in the mitochondria via MCU, thus causing paraptosis in MDA-MB-231 breast cancer cells.

Dilshara, Matharage Gayani; Molagoda, Ilandarage Menu Neelaka; Jayasooriya, Rajapaksha Gedara Prasad Tharanga; Choi, Yung Hyun; Park, Cheol; Kim, Gi-Young;

2021-02-01

https://doi.org/10.1016/j.abb.2020.108723