Nutlin-3 enhances the bortezomib sensitivity of p53-defective cancer cells by inducing paraptosis.
- Author:
Dong Min LEE
1
;
In Young KIM
;
Min Ji SEO
;
Mi Ri KWON
;
Kyeong Sook CHOI
Author Information
- Publication Type:Original Article
- MeSH: Bortezomib*; Cell Death; Endoplasmic Reticulum; Homeostasis; Humans; Mitochondria; Proteasome Inhibitors; Up-Regulation
- From:Experimental & Molecular Medicine 2017;49(8):e365-
- CountryRepublic of Korea
- Language:English
- 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.
