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Carcinogenesis Advance Access originally published online on July 3, 2009
Carcinogenesis 2009 30(9):1517-1527; doi:10.1093/carcin/bgp165
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Ozgur Kutuk1, Elif Damla Arisan1, Tugsan Tezil1, Maria C. Shoshan2 and Huveyda Basaga1,*

1 Biological Sciences and Bioengineering Program, Sabanci University, 34956 Tuzla, Istanbul, Turkey
2 Department of Oncology-Pathology, CCK R8:03, Karolinska Institute, S-17176 Stockholm, Sweden

* To whom correspondence should be addressed. Tel: +90 216 483 9511; Fax: +90 216 483 9550; Email: huveyda{at}sabanciuniv.edu

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-xL 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.

Abbreviations: ELISA, enzyme-linked immunosorbent assay; MMP, mitochondrial membrane potential; PCR, polymerase chain reaction; ROS, reactive oxygen species; RT, reverse transcription; siRNA, small interfering RNA; 4-HNE, 4-hydroxynonenal

Received January 21, 2009; revised May 27, 2009; accepted June 27, 2009.


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