SERPINB3 protects from oxidative damage by chemotherapeutics through inhibition of mitochondrial respiratory complex I
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Francesco Ciscato1,2 Marco Sciacovelli1,3, Gianmarco Villano2, Cristian Turato2, Paolo Bernardi1, Andrea Rasola1, Patrizia Pontisso2
1 CNR Institute of Neuroscience and Department of Biomedical Sciences, University of Padova, Padova, Italy;
2 Department of Medicine, University of Padova, Padova, Italy
3 present address: Medical Research Council Cancer Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge, United Kingdom
Andrea Rasola, email:
Keywords: SERPINB3; chemotherapeutics; mitochondria; respiratory complexes; reactive oxygen species; cell death
Received: September 13, 2013 Accepted: December 24, 2013 Published: December 24, 2013
SERPINB3 (SB3) is a serine protease inhibitor overexpressed in several malignancies of epithelial origin, including primary liver cancer, where it inhibits apoptosis through poorly defined mechanisms. In the present study we analyze the effect of SB3 on hepatoma cell death elicited by a panel of chemotherapeutic agents. We report that SB3 shields cells from the toxicity of drugs with a pro-oxidant action such as doxorubicin, cisplatin and EM20-25. The rapid rise in ROS levels prompted by these compounds causes opening of the mitochondrial permeability transition pore (PTP), irreversibly committing cells to death. We find that a fraction of SB3 locates in mitochondrial inner compartments, and that this mitochondrial fraction increases under conditions of oxidative stress. Mitochondrial SB3 inhibits ROS generation and the ensuing PTP induction and cell death through an inhibitory interaction with respiratory Complex I. These findings identify a novel mechanism of action of SB3 that contributes to tumor cell resistance to anti-neoplastic drugs
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