Proteins inside cells called “chaperones” are intimately involved in helping cells respond to environmental stressors. They may also prove to be an Achilles heel for targeting cancer cells, which rely even more heavily on chaperone proteins than normal cells do.
To study how cells respond to environmental stress, molecular biologist Georgios Karras has joined the faculty of The University of Texas MD Anderson Cancer Center. He was recruited in 2018 from the Whitehead Institute for Biomedical Research, in Cambridge, Mass., where he was a postdoctoral fellow, with the help of a First-Time Tenure-Track Award from CPRIT.
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Proteins inside cells called “chaperones” are intimately involved in helping cells respond to environmental stressors. They may also prove to be an Achilles heel for targeting cancer cells, which rely even more heavily on chaperone proteins than normal cells do.
To study how cells respond to environmental stress, molecular biologist Georgios Karras has joined the faculty of The University of Texas MD Anderson Cancer Center. He was recruited in 2018 from the Whitehead Institute for Biomedical Research, in Cambridge, Mass., where he was a postdoctoral fellow, with the help of a First-Time Tenure-Track Award from CPRIT.
Chaperone proteins help cells respond to stress in several ways, including binding to damaged proteins when the cellular environment is disrupted — like when a cell is exposed to excessive heat, for example. Proteins are flexible strings of amino acids when they are first synthesized, and chaperone proteins help them fold correctly and get them where they need to go inside the cell. Proper folding of a protein is crucial to the protein’s function.
“We’re focused on Heat Shock Protein 90, an essential chaperone protein that makes up 2% of our proteome,” Karras says. “It’s so abundant in eukaryotes that you can turn it down ten-fold and still get viable organisms. The excess allows it to work as quantitative environmental sensor, and inhibiting it renders the cell or even the whole organism vulnerable to a wide variety of environmental stressors.”
Environmental factors as simple as the foods we eat and common drugs we take can affect the amount and performance of HSP-90. Karras is studying how mustering the chaperone proteins may be beneficial in some cases, and depleting them may help in other situations.
Patients born with mutations in DNA-repair proteins associated with the genetic disease Fanconi anemia often develop cancer early in life. People whose inherited mutant proteins bind to HSP-90 generally have a milder form of the disease, because the chaperone enables the defective protein to fold properly and function in spite of its defects. Karras speculates that enhancing the function of HSP-90, through pharmaceuticals, food or lifestyle choices, help protect these patients from developing cancer quite so soon.
On the flip side, they should avoid exposure to things that suppress the function of HSP-90. “If these people were exposed to HSP-90 inhibitors early in life, they might develop a much more severe phenotype,” Karras says. “We are developing tools to identify individuals who are especially sensitive to HSP-90 inhibitors, focusing on Fanconi anemia and cancer patients.”
Cancer cells accumulate many mutations in their genes, many of which are detrimental to the encoded proteins. These damaged cells are overly reliant on abundant chaperone proteins to ensure that the defective proteins function. But HSP-90 distinguishes itself from other chaperone proteins; it helps cancer cells evolve resistance to chemotherapy.
“There is no drug that doesn’t eventually get thwarted by cancer in terms of resistance,” Karras says. In model systems, including cultured human cancer cells and yeast, he’s trying to understand how affecting the function of HSP-90 might improve cancer treatment.
He’s also using chaperone proteins to understand the severity of mutations. Cancer cells often contain many different genetic mutations, but distinguishing which mutations are important is challenging. But in his model system, he can test which proteins bind tightly to different types of chaperone proteins, and discover which mutations are likely to cause problematic phenotypes.
Karras received his undergraduate education at Democritus University of Thrace, in Alexandroupolis, Greece, and his Ph.D. from the Max Plank Institute of Biochemistry in Martinsried, Germany. In 2011 he came to the Whitehead Institute as a postdoctoral fellow.
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