Biochemistry, Biophysics, and Structural Biology | Open Access Articles

Intraperitoneal Nanotherapy For Metastatic Ovarian Cancer Based On Sirna-Mediated Suppression Of Dj-1 Protein Combined With A Low Dose Of Cisplatin, Canan Schumann, Stephanie Chan, Jess A. Miller, Yuliya Bortnyak, Katherine Carey, Alex Fedchyk, Leon Wong, Tetiana Korzun, Abraham S. Moses, Anna Lorenz, Delany Shea, Olena Taratula, Oleh Khalimonchuk, Oleh Taratula

Department of Biochemistry: Faculty Publications

Herein, we report an efficient combinatorial therapy for metastatic ovarian cancer based on siRNA-mediated suppression of DJ-1 protein combined with a low dose of cisplatin. DJ-1 protein modulates, either directly or indirectly, different oncogenic pathways that support and promote survival, growth, and invasion of ovarian cancer cells. To evaluate the potential of this novel therapy, we have engineered a cancer-targeted nanoplatform and validated that DJ-1 siRNA delivered by this nanoplatform after intraperitoneal injection efficiently downregulates the DJ-1 protein in metastatic ovarian cancer tumors and ascites. In vivo experiments revealed that DJ-1 siRNA monotherapy outperformed cisplatin alone by inhibiting tumor growth …

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Use Of Cysteine-Reactive Crosslinkers To Probe Conformational Flexibility Of Human Dj-1 Demonstrates That Glu18 Mutations Are Dimers, Janani Prahlad, David N. Hauser, Nicole M. Milkovic, Mark R. Cookson, Mark A. Wilson

Department of Biochemistry: Faculty Publications

The oxidation of a key cysteine residue (Cys106) in the parkinsonism-associated protein DJ-1 regulates its ability to protect against oxidative stress and mitochondrial damage. Cys106 interacts with a neighboring protonated Glu18 residue, stabilizing the Cys106-SO₂ ⁻ (sulfinic acid) form of DJ-1. To study this important post-translational modification, we previously designed several Glu18 mutations (E18N, E18D, E18Q) that alter the oxidative propensity of Cys106. However, recent results suggest these Glu18 mutations cause loss of DJ-1 dimerization, which would severely compromise the protein’s function. The purpose of this study was to conclusively determine the oligomerization state of these mutants using X-ray …

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Conservation Of Oxidative Protein Stabilization In An Insect Homologue Of The Parkinsonism-Associated Protein Dj-1, Jiusheng Lin, Janani Prahlad, Mark A. Wilson

Department of Biochemistry: Faculty Publications

DJ-1 is a conserved, disease-associated protein that protects against oxidative stress and mitochondrial damage in multiple organisms. Human DJ-1 contains a functionally essential cysteine residue (Cys106) whose oxidation is important for regulating protein function by an unknown mechanism. This residue is well conserved in other DJ-1 homologues, including two (DJ-1α and DJ-1β) in Drosophila melanogaster. Because D. melanogaster is a powerful model system for studying DJ-1 function, we have determined the crystal structure and impact of cysteine oxidation on Drosophila DJ-1β. The structure of D. melanogaster DJ-1β is similar to that of human DJ-1, although two important residues in …

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Department of Biochemistry: Faculty Publications

Use Of Cysteine-Reactive Crosslinkers To Probe Conformational Flexibility Of Human Dj-1 Demonstrates That Glu18 Mutations Are Dimers, Janani Prahlad, David N. Hauser, Nicole M. Milkovic, Mark R. Cookson, Mark A. Wilson

Department of Biochemistry: Faculty Publications

Conservation Of Oxidative Protein Stabilization In An Insect Homologue Of The Parkinsonism-Associated Protein Dj-1, Jiusheng Lin, Janani Prahlad, Mark A. Wilson

Department of Biochemistry: Faculty Publications