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Cisplatin overcomes Bcl-2-mediated resistance to apoptosis via preferential engagement of Bak: critical role of Noxa-mediated lipid peroxidation

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Author
Kütük, Özgür
Arısan, Elif Damla
Tezil, Tuğsan
Shoshan, Maria C.
Başağa, Hüveyda
Type
Article
Date
2009-09-01
Language
en_US
Metadata
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Abstract
Increased expression of antiapoptotic Bcl-2 proteins confers therapeutic resistance in various cancer types. Targeting Bcl-2 proteins by small molecules or activating alternative pathways to bypass Bcl-2-mediated protection to promote apoptosis are two approaches to overcoming therapeutic resistance. Here, we show that cisplatin triggers a Bak-dependent pathway to induce apoptosis in Bcl-2-overexpressing MCF-7 cells. p53-mediated induction of Noxa expression, generation of lipid peroxidation end products and induction of Noxa–Mcl-1 interaction are necessary for this pathway to function. Although Puma is also induced by cisplatin treatment, it is not required for apoptosis. Similarly, reactive oxygen species production by cisplatin did not have any effect on cisplatin-induced apoptosis in MCF-7 Bcl-2 cells. Furthermore, p53 promotes cisplatin-induced apoptosis by directly binding and counteracting Bcl-x L antiapoptotic function. In conclusion, our findings suggest a novel mode of action for cisplatin to overcome Bcl-2-mediated protection against apoptosis, which requires preferential activation of Bak and p53-mediated upregulation of Noxa protein levels and lipid peroxidation.
Subject
INDUCED CELL-DEATH
OXIDATIVE STRESS
CANCER-CELLS
MITOCHONDRIAL APOPTOSIS
BH3-ONLY PROTEINS
HYDROGEN-PEROXIDE
IN-VIVO
BCL-2
P53
ACTIVATION
apoptosis
cisplatin
bcl2 gene
lipid peroxidation
mcf-7 cells
Cancer Biology
URI
https://doi.org/10.1093/carcin/bgp165
https://hdl.handle.net/11413/4487
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  • Makaleler / Articles [140]

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İstanbul Kültür University

Hakkında |Politika | Kütüphane | İletişim | Send Feedback | Admin

Istanbul Kültür University, Ataköy Campus E5 Karayolu Üzeri Bakırköy 34158, İstanbul / TURKEY
Copyright © İstanbul Kültür University

Creative Commons Lisansı
IKU Institutional Repository, Creative Commons Alıntı-GayriTicari-Türetilemez 4.0 Uluslararası Lisansı ile lisanslanmıştır.

Designed by  UNIREPOS