PLOS Science Wednesday: We’re Nicholas Heintz, Brian Cunniff, and Kim Nelson, and we recently published a PLOS ONE study showing that selective targeting of two related antioxidant enzymes causes mesothelioma cancer cells to choke on their own oxidative exhaust – Ask Us Anything!

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Hi Reddit,

My name is Nicholas Heintz and I am a Professor of Pathology at the University of Vermont Cancer Center. My research has focused on dysregulation of redox signaling in cancer cells, and how the enhanced production of reactive oxygen species (ROS) in tumor cell mitochondria can be exploited for therapeutic purposes in aggressive human malignancies like mesothelioma. My coauthors Brian Cunniff (a former graduate student in my lab), and Kim Nelson (a postdoctoral fellow at Wake Forest) are joining me for this AMA.

My name is Brian Cunniff and I am a Postdoctoral Research Fellow at Harvard Medical School. My research focuses on intracellular trafficking, specifically clathrin mediated endocytosis, during cell migration and tissue organization. Using cutting-edge lattice light sheet microscopy we are able to visualize cellular processes with unprecedented spatial and temporal resolution.

My name is Kim Nelson and I am junior faculty in the Chemistry Department at Wake Forest University. I have been part of a highly collaborative, interdisciplinary team of researchers at Wake Forest who are focused on elucidating how reactive oxygen species are produced in a regulated manner as part of cell signaling events involved in growth, cell division, and cell death. My research has focused on 1) the kinetic, biophysical, and structural analysis of features in the peroxiredoxin family of proteins that modulate their rapid reaction with peroxide and 2) the identification, visualization, and biochemical analysis of proteins that are functionally modified by cysteine oxidation in response to regulated, intracellular hydrogen peroxide production. Along with Todd Lowther, my contribution to this study was in utilizing structural, kinetics and mass spectrometry analyses to characterize the mechanism by which thiostrepton directly associated with and inhibited the activity of purified human Peroxiredoxin 3.

We recently published a research study titled “Disabling mitochondrial peroxide metabolism via combinatorial targeting of peroxiredoxin 3 as an effective therapeutic approach for malignant mesothelioma” in PLOS ONE. In this paper we show that the thiazole antibiotic thiostrepton covalently crosslinks the antioxidant protein peroxiredoxin 3, thereby inactivating its activity. Since peroxiredoxin 3 is largely responsible for metabolizing the copious amounts of ROS produced by mitochondria in human mesothelioma cells, inactivation induces intolerable levels of mitochondrial oxidative stress and tumor cell death. When paired with gentian violet, which blocks expression of another antioxidant enzyme in the peroxiredoxin 3 pathway, thiostrepton markedly inhibits tumor growth in mouse models of human mesothelioma.

This work extends our previous observations published in PLOS ONE, “Peroxiredoxin 3 is a redox-dependent target of thiostrepton in malignant mesothelioma cells”; which showed that the activity of thiostrepton is dependent on the redox state of the cell, thereby explaining the preferential effects of the drug on highly malignant tumor cells that commonly produce large amounts of ROS. Our paper, along with many other recent studies, identifies pro-oxidant therapeutic approaches as viable treatments for intractable tumors.

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">PLOS Science Wednesday: We’re Nicholas Heintz, Brian Cunniff, and Kim Nelson, and we recently published a PLOS ONE study showing that selective targeting of two related antioxidant enzymes causes mesothelioma cancer cells to choke on their own oxidative exhaust – Ask Us Anything!