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Nutlin-3 Enhances the Bortezomib Sensitivity of p53-defective Cancer Cells by Inducing Paraptosis

Nutlin-3 Enhances the Bortezomib Sensitivity of p53-defective Cancer Cells by Inducing Paraptosis

Dong Min Lee, In Young Kim, Min Ji Seo, Mi Ri Kwon, Kyeong Sook Choi

Exp Mol Med. 2017 Aug 11;49(8):e365.

PMID: 28798402

Abstract:

The proteasome inhibitor, bortezomib, is ineffective against many solid tumors. Nutlin-3 is a potent antagonist of human homolog of murine double minute 2/p53 interaction exhibiting promising therapeutic anti-cancer activity. In this study, we show that treatment of various p53-defective bortezomib-resistant solid tumor cells with bortezomib plus nutlin-3 induces paraptosis, which is a cell death mode accompanied by dilation of the endoplasmic reticulum (ER) and mitochondria. Bortezomib alone did not markedly alter cellular morphology, and nutlin-3 alone induced only a transient mitochondrial dilation. However, bortezomib/nutlin-3 co-treatment triggered the progressive fusion of swollen ER and the formation of megamitochondria, leading to cell death. Mechanistically, proteasomal-impairment-induced ER stress, CHOP upregulation and disruption of Ca2+ homeostasis were found to be critically involved in the bortezomib/nutlin-3-induced dilation of the ER. Our results further suggest that mitochondrial unfolded protein stress may play an important role in the mitochondrial dilation observed during bortezomib/nutlin-3-induced cell death. Collectively, these findings suggest that bortezomib/nutlin-3 perturbs proteostasis, triggering ER/mitochondria stress and irrecoverable impairments in their structure and function, ultimately leading to paraptotic cell death.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP548472680	Nutlin-3		548472-68-0	Price

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