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

• Published in: Experimental & molecular medicine 2017, 49(0), , pp.1-18
• Main Authors: 이동민, 김인영, 서민지, 권미리, 최경숙
• Format: Article
• Language: English
• Subjects: 생화학
• ISSN: 1226-3613; 2092-6413

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. KCI Citation Count: 7