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SERPINB3 protects from oxidative damage by chemotherapeutics through inhibition of mitochondrial respiratory complex
Francesco Ciscato1, Marco Sciacovelli, Gianmarco Villano
1CNR Institute of Neuroscience and Department of Biomedical Sciences, University of Padova, Padova, Italy;
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.
Insights
Serine protease inhibitor SERPINB3 (SB3) protects cancer cells from chemotherapy by accumulating in mitochondria. It inhibits Complex I, preventing oxidative stress and cell death, thus promoting tumor resistance.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Serine protease inhibitor SERPINB3 (SB3) is overexpressed in epithelial cancers, including liver cancer.
- SB3 is known to inhibit apoptosis via poorly understood mechanisms, contributing to chemoresistance.
Purpose of the Study:
- To investigate the effect of SB3 on hepatoma cell death induced by chemotherapeutic agents.
- To elucidate the mechanism by which SB3 confers resistance to anti-cancer drugs.
Main Methods:
- Hepatoma cell culture treated with doxorubicin, cisplatin, and EM20-25.
- Analysis of reactive oxygen species (ROS) levels and mitochondrial permeability transition pore (PTP) opening.
- Subcellular localization studies of SB3, including under oxidative stress.
- Assessment of SB3 interaction with mitochondrial respiratory Complex I.
Main Results:
- SB3 confers resistance to pro-oxidant chemotherapeutic drugs like doxorubicin, cisplatin, and EM20-25.
- SB3 localizes to mitochondria, with increased levels under oxidative stress.
- Mitochondrial SB3 inhibits ROS generation and PTP opening by interacting with respiratory Complex I.
- This interaction prevents chemotherapy-induced cell death.
Conclusions:
- SB3's mitochondrial localization and interaction with Complex I represent a novel mechanism of chemoresistance.
- SB3 contributes to tumor cell survival by mitigating drug-induced oxidative stress and apoptosis.
- Targeting mitochondrial SB3 may represent a strategy to overcome chemoresistance in epithelial cancers.
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