Bar Harbor, Maine – Exploiting one characteristic of cancer—proteomic instability—could be a way of combating that very cancer, a Jackson Laboratory research team led by Chengkai Dai, M.D., Ph.D., reports.
Every cell in the human body is a protein manufacturing plant. So-called heat-shock proteins help to supervise the protein-building process, ensuring their correct folding, transporting them to their proper destinations and eliminating faulty or degraded proteins.
Environmental stresses such as excessive heat, poisons or oxidative stress cause cells to produce more heat-shock proteins, which helps to counter proteomic instability and to endure stress. That, as the Dai lab reported in 2007, enables tumors to grow and survive.
In a featured article published in the Feb. 12 issue in the journal Cell, Dai and colleagues delved deeper into the relationship between protein instability and cancer.
The RAS-RAF-MEK-ERK signaling pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the cell’s nucleus. The researchers discovered that the HSF1 (heat-shock factor 1) protein is part of this vital chain.
When the inhibition of MEK in cancer cells inactivates HSF1, “proteomic chaos” results: protein destabilization, aggregation and the production of amyloids, a major culprit in human neurodegenerative disorders such as Alzheimer’s disease. And though the protein destabilization is a hallmark of cancer, the production of amyloids actually suppresses tumors.
The researchers showed that the warped signaling pathway in tumors protects the tumor’s protein stability and suppresses amyloid production. The findings suggest a potential therapeutic strategy in disrupting tumors’ fragile proteome equilibrium and thereby promoting tumor-suppressing amyloid production.
“Our proof-of-concept experiments suggest that intrinsic proteomic instability associated with a malignant state may be exploited to combat cancer,” Dai says. “Excitingly, cancer cells are particularly vulnerable to amyloid induction than their normal counterparts.”
The Jackson Laboratory is an independent, nonprofit biomedical research institution and National Cancer Institute-designated Cancer Center based in Bar Harbor, Maine, with a facility in Sacramento, Calif., and a new genomic medicine institute in Farmington, Conn. It employs more than 1,600 staff, and its mission is to discover precise genomic solutions for disease and empower the global biomedical community in the shared quest to improve human health.
Tang et al.: "MEK guards proteome stability and inhibits tumor-suppressive amyloidogenesis via HSF1." Cell, 160(4):729-744.
This work was supported in part by The Jackson Laboratory Cancer Center
Support Grant (3P30CA034196), and grants from NIH (1DP2OD007070) and the Ellison Medical Foundation (AS-NS-0599-09).
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