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SERPINB3 Protects From Oxidative Damage by Chemotherapeutics Through Inhibition of Mitochondrial Respiratory Complex I

SERPINB3 Protects From Oxidative Damage by Chemotherapeutics Through Inhibition of Mitochondrial Respiratory Complex I

Francesco Ciscato, Marco Sciacovelli, Gianmarco Villano, Cristian Turato, Paolo Bernardi, Andrea Rasola, Patrizia Pontisso

Oncotarget. 2014 May 15;5(9):2418-27.

PMID: 24810714

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP141266446	EM20-25		141266-44-6	Price

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