title: Probing novel roles of the mitochondrial uniporter in ovarian cancer cells using nanoparticles.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Rochelle R
authors.initials: RR
authors.lastname: Arvizo
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Moyano
authors.forename: Sounik
authors.initials: S
authors.lastname: Saha
authors.forename: Michael A
authors.initials: MA
authors.lastname: Thompson
authors.forename: Resham
authors.initials: R
authors.lastname: Bhattacharya
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Rotello
authors.forename: Y S
authors.initials: YS
authors.lastname: Prakash
authors.forename: Priyabrata
authors.initials: P
authors.lastname: Mukherjee
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006046:Gold / Q000494:pharmacology*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D053768:Metal Nanoparticles / Q000737:chemistry*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms
chemical_list: D000970:Antineoplastic Agents; D002135:Calcium-Binding Proteins; D027682:Cation Transport Proteins; C116241:MICU1 protein, human; D033681:Mitochondrial Membrane Transport Proteins; D006046:Gold; D002118:Calcium
keywords: Apoptosis; Bcl-2; Cancer; Cancer Biology; Caspase; Mitochondrial Apoptosis