Nutlin-3 enhances the bortezomib sensitivity of p53-defective cancer cells by inducing paraptosis
Experimental & Molecular Medicine
;
: e365-2017.
Article
in English
| WPRIM
| ID: wpr-174859
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.
Full text:
Available
Index:
WPRIM (Western Pacific)
Main subject:
Up-Regulation
/
Cell Death
/
Endoplasmic Reticulum
/
Proteasome Inhibitors
/
Bortezomib
/
Homeostasis
/
Mitochondria
Type of study:
Diagnostic study
Limits:
Humans
Language:
English
Journal:
Experimental & Molecular Medicine
Year:
2017
Type:
Article
Similar
MEDLINE
...
LILACS
LIS