Protein That Kills Cells in Neurodegenerative Diseases Implicated in Cancer Cell Metabolism

New research from the University of Central Florida has shed light on the workings of a particular protein found in the human body that could have future implications for the treatment of cancer and neurodegenerative conditions.

Previous research by Maria C. Franco and Alvaro Estevez of the Burnett School of Biomedical Sciences at UCF’s College of Medicine showed that a modified version of a protein known as “heat shock protein 90” or Hsp90 is a trigger for killing cells in the nervous system in neurodegenerative disorders.

Now, Franco’s latest findings show that Hsp90 doesn’t treat all cells the same. In fact, the same protein that kills some cells may help cancer cells, according to research published in the Journal of Biological Chemistry on July 31.

“We have found a protein that is modified only in pathological conditions,” said Franco, an assistant scientist at the Burnett School who led the research team. “In the nervous system, it is toxic to the cells that are affected by neurodegenerative diseases, while in tumor cells it may actually be acting as a pro-survival agent. In both cases, targeting this oxidized protein may be a potential therapeutic alternative.”

Hsp90 is one of the most studied proteins in terms of potential cancer-fighting drugs, but progress has been slow. Franco’s work provides more clarity on the complex nature of the protein’s impact on cells.

Her research team discovered that a nitration of Hsp90 limits oxygen to the cell’s mitochondria, decreasing its energy production. It sounds like a death knell for the cell, but the reduction of oxygen consumption may actually help the cancerous cells by increasing their resistance to hypoxia since these cells rely on other energy sources.

This image shows the Hsp90 chaperone cycle.

Hsp90 is one of the most studied proteins in terms of potential cancer-fighting drugs, but progress has been slow. This image is for illustrative purpopses only and the diagram shows the Hsp90 chaperone cycle.

Franco has been studying the role of Hsp90 and other oxidized proteins in the regulation of cellular metabolism for the past eight years, with the goal of identifying new targets for drugs to combat tumor cells. She is eager to find ways to combat tumor cells while keeping healthy cells intact.

A native of Buenos Aires, Franco has been at UCF for the past five years and has multiple degrees from the University of Buenos Aires. She completed post-doctoral work at Cornell University and Oregon State University.

Franco’s other work focuses on free radicals, oxidative stress and mitochondrial metabolism.

About this cancer research

Other collaborators on the project include Cassandra N. Dennys, Pascal A. Nelson and Alvaro G. Estevez from UCF; Karina C. Ricart and Aimee Landar from the University of Alabama at Birmingham; Analia S. Gonzales from Laboratory of Oxygen Metabolism at the University of Buenos Aire; Michael S. Janes from ThermoFisher Scientific in Eugene, Oregon; and Ryan A. Mehl from Oregon State University.

Funding: The study was funded in part with National Institutes of Health Grant NS36761.

Source: Mark Schlueb – University of Central Florida
Image Source: The image is in the public domain
Original Research: Abstract for “Nitration of Hsp90 on Tyrosine 33 Regulates Mitochondrial Metabolism” by Maria C. Franco, Karina C. Ricart, Analía S. Gonzalez, Cassandra N. Dennys, Pascal A. Nelson, Michael S. Janes, Ryan A. Mehl, Aimee Landar, and Alvaro G. Estévez in Journal of Biological Chemistry. Published online June 17 2015 doi:10.1074/jbc.M115.663278


Abstract

Nitration of Hsp90 on Tyrosine 33 Regulates Mitochondrial Metabolism

Peroxynitrite production and tyrosine nitration are present in several pathological conditions, including neurodegeneration, stroke, aging, and cancer. Nitration of the pro-survival chaperone heat shock protein 90 (Hsp90) in position 33 and 56 induces motor neuron death through a toxic gain-of-function. Here we show that nitrated Hsp90 regulates mitochondrial metabolism independently of the induction of cell death. In PC12 cells, a small fraction of nitrated Hsp90 was located on the mitochondrial outer membrane and down-regulated mitochondrial membrane potential, oxygen consumption, and ATP production. Neither endogenous Hsp90 present in the homogenate nor unmodified and fully active recombinant Hsp90 was able to compete with the nitrated protein for the binding to mitochondria. Moreover, endogenous or recombinant Hsp90 did not prevent the decrease in mitochondrial activity but supported nitrated Hsp90 mitochondrial gain-of-function. Nitrotyrosine in position 33, but not in any of the other four tyrosine residues prone to nitration in Hsp90, was sufficient to down-regulate mitochondrial activity. Thus, in addition to induction of cell death, nitrated Hsp90 can also regulate mitochondrial metabolism, suggesting that depending on the cell type, distinct Hsp90 nitration states regulate different aspects of cellular metabolism. This regulation of mitochondrial homeostasis by nitrated Hsp90 could be of particular relevance in cancer cells.

“Nitration of Hsp90 on Tyrosine 33 Regulates Mitochondrial Metabolism” by Maria C. Franco, Karina C. Ricart, Analía S. Gonzalez, Cassandra N. Dennys, Pascal A. Nelson, Michael S. Janes, Ryan A. Mehl, Aimee Landar, and Alvaro G. Estévez in Journal of Biological Chemistry. Published online June 17 2015 doi:10.1074/jbc.M115.663278

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