Work

Probing Novel Roles of the Mitochondrial Uniporter in Ovarian Cancer Cells Using Nanoparticles

Year: 2013

Type: article

Abstract: Nanoparticles provide a potent tool for targeting and understanding disease mechanisms. In this regard, cancer cells are surprisingly resistant to the expected toxic effects of positively charged gold nanoparticles ( + AuNPs). Our investigations led to the identification of MICU1, regulator of mitochondrial calcium uniporter, as a key molecule conferring cancer cells with resistance to + AuNPs. The increase in cytosolic [Ca 2+ ] cyto in malignant cells induced by + AuNPs is counteracted by MICU1, preventing cell death. Pharmacological or siRNA-mediated inhibition of mitochondrial Ca +2 entry leads to endoplasmic reticulum stress and sensitizes cancer cells to + AuNP-induced cytotoxicity. Silencing MICU1 decreases Bcl-2 expression and increases caspase-3 activity and cytosolic cytochrome c levels, thus initiating the mitochondrial pathway for apoptosis: effects further enhanced by + AuNPs. This study highlights the potential of nanomaterials as a tool to broaden our understanding of cellular processes, establishes MICU1 as a novel regulator of the machinery in cancer cells that prevents apoptosis, and emphasizes the need to synergize nanoparticle design with understanding of mitochondrial machinery for enhancing targeted cellular toxicity. Background: The mechanisms underlying resistance of ovarian cancer cells to apoptosis by positively charged gold nanoparticles ( + AuNPs) are unknown. Results: MICU1 silencing stimulated mitochondrial membrane depolarization in the presence of + AuNPs, leading to apoptosis. Conclusion: MICU1 confers cellular resistance to apoptosis. Significance: This study suggests that MICU1 may be an important regulator of apoptotic resistance machineries in cancer cells.

Source: Journal of Biological Chemistry

DOI: 10.1074/jbc.m112.435206