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Exp Mol Med. 2017 Aug 11;49(8):e365. doi: 10.1038/emm.2017.112.

Nutlin-3 enhances the bortezomib sensitivity of p53-defective cancer cells by inducing paraptosis.

Lee DM1,2, Kim IY1,2, Seo MJ1,2, Kwon MR1,2, Choi KS1,2.

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Department of Biochemistry, Ajou University School of Medicine, Suwon, Korea.
BK21 Plus Program, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, Korea.


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.

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