Department of Pathology
Heintz Lab Research
Research: To exploit perturbations in redox signaling to develop new therapeutic approaches to treat malignant mesothelioma and other solid tumor types.
Education: To improve interdisciplinary opportunities for graduate education in the biomedical sciences. Administration: To provide a contemporary and productive environment for the pursuit of cancer research across the UVM campus.
Overview of current areas of research and approaches
Redox signaling in cancer biology: For many years it has been known that reactive oxygen species (ROS) influence cell differentiation, cell proliferation, and cell survival through redox-dependent signaling pathways. The oxidation state of reactive cysteine residues in transcription factors, phosphatases, kinases, enzymes and regulatory factors are molecular targets for ROS, and mediate responses to both exogenous and endogenous oxidants over a broad range ROS concentrations. We have extensively explored the role of peroxiredoxins (Prxs), a family of highly conserved and ubiquitously expressed peroxidases, in cell cycle control. Prxs are unique in that they are highly susceptible to inactivation by hydrogen peroxide due to hyper-oxidation of the peroxidatic cysteine to sulfinic acid, a post-translational modification that is reversible by sulfiredoxin. Prxs interact and control the activity of many cell cycle factors, including c-Myc, PTEN, and PDGFR, suggesting that they act as redox sensors that govern the strength and duration of signaling. Studies in human malignant mesothelioma cell lines indicates that tumorigenesis involves adaptation to chronic oxidative stress, with alterations in the expression of Prxs, other antioxidant enzymes, and cell cycle transcription factors such as FoxM1. FoxM1 is of particular interest because it responds to oxidative stress and regulates the expression of protective factors such as PrxIII, a mitochondrial peroxidase that is over-expressed in many tumor types. Our most recent studies indicate that PrxIII is a promising therapeutic target in malignant mesothelioma. Studies with two novel chemotherapeutic agents that act together to impair PrxIII activity and selectively kill mesothelioma cells are underway. Because it is a common feature of many tumors, and is largely independent of specific alterations in tumor suppressor genes and oncogenes, we consider oxidant metabolism a promising target in cancer therapy. Our efforts are now directed toward devising therapeutic interventions that exploit perturbations in oxidant metabolism in tumor cells while leaving normal cells unaffected. We thank the Lake Champlain Cancer Research Organization and the John Sterling Memorial Grant from the Mesothelioma Applied Research Foundation for support.
Laboratory expertise: We employ a wide variety of state–of-the-art cell and molecular biological and biochemical approaches, including high resolution imaging, manipulation of gene expression, animal models and translational studies with human tissues, to address specific questions in tumor cell biology. We actively collaborate with laboratories here and around the world to examine the mechanisms by which reactive oxygen species influence cell proliferation, cell differentiation and cell death. We are particularly adept at examining the function of transcription factors that control cell cycle and cell fate decisions. We participate in educational and research opportunities in the Environmental Pathology Program and Vermont Cancer Center, and travel to international conferences to present our work.
My laboratory is interested in the molecular mechanisms by which cells regulate cell proliferation and cell death in response to environmental agents. Our most recent efforts have focused on the effect of oxidative stress on cell cycle control, with an emphasis on redox-dependent signaling pathways that regulate expression of cyclin D1 during cell cycle re-entry. Chronic exposure to environmental agents such as cigarette smoke, noxious gases, and airborne particulates induces oxidative stress, which over time leads to phenotypic adaptations that perturb cell cycle control, cell differentiation, cell death pathways and tissue function. We are particularly interested in the mechanisms by which reactive oxygen species influence redox-responsive cell signaling pathways that control cell proliferation, and how these cell signaling pathways are corrupted in cancer cells. We are particularly interested in the interplay between oxidation-reduction cycles in specific signaling proteins and a class of ubiquitous peroxidases called peroxiredoxins (Prxs). We are investigating a number of anti-cancer drugs that interact directly with Prxs or influence the activity of NADPH oxidases (NOXes), one source of ROS that drive mitogenesis. Recently we have focused on factors that regulate ROS production in mitochondria, including the mitochondrial oxidase NOX4 and the peroxiredoxin PrxIII. Our aim is to investigate perturbations in oxidant metabolism as a therapeutic target in intractable cancers such as mesothelioma.
- Phalen TJ, Weirather K, Deming PB, Anathy V, Howe AK, van der Vliet A, Jonsson T, Poole LB, and Heintz NH: Oxidation state governs structural transitions in peroxiredoxin II that correlate with cell cycle arrest and recovery. J Cell Biol 175:779-789, 2006 PMCID: PMC2064677
- Haraldson JD, Liu G, Botting CH, Walton JGA, Storm J, Phalen TJ, Kwok LY, Soldati-Favre D, Heintz NH, Muller S, Westwood NJ, and Ward GE: Identification of conoidin A as a covalent inhibitor of peroxiredoxin II. Org Biomol Chem 7:3040-3048, 2009 PMCID: PMC3043594
- Shukla A, Bosenberg MW, MacPherson MB, Butnor KJ, Heintz NH, Pass HI, Carbone M, Testa JR and Mossman BT: Activated CREB is overexpressed in human mesotheliomas and inhibits apoptosis. Am J Pathol 175:2197-2206, 2009 PMCID: PMC2774081
- Odell ID, Newick K, Heintz NH, Wallace SS, and Pederson DS: Non-specific DNA binding interferes with the efficient excision of oxidative lesions from chromatin by the human DNA glycosylase, NEIL1. DNA Repair 9:134-143, 2010 PMCID: PMC2829949
- Hyde S, Eckenroth B, Smith B, Eberley W, Heintz N, Jackman J, and Doublié S: THG1, a unique 3'-5' nucleotidyltransferase, shares unexpected structural homology with canonical 5'-3' DNA polymerases. Proc Natl Acad Sci U S A 107:20305-20310, 2010 PMCID: PMC2996709
Last modified June 11 2012 12:19 PM