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Carcinogenesis Advance Access published online on July 3, 2009
Carcinogenesis, 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

Corresponding Author: Huveyda Basaga, Biological Sciences and Bioengineering Program, Sabanci University, 34956, Tuzla, Istanbul, Turkey. e-mail: huveyda{at}sabanciuniv.edu, Phone: +902164839511 Fax: +902164839550

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, ROS 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.

Key Words: cisplatin • Bcl-2 • apoptosis • p53 • Noxa • lipid peroxidation

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


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