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

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

• Lee DM
• Kim IY
• Seo MJ
• Kwon MR
• Choi KS

• KMID: 2389293
• DOI: http://doi.org/10.1038/emm.2017.112

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 Ca²âº 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.

MeSH Terms

Bortezomib*
Cell Death
Endoplasmic Reticulum
Homeostasis
Humans
Mitochondria
Proteasome Inhibitors
Up-Regulation
Bortezomib
Proteasome Inhibitors