Researchers find new tumor suppressor destroys a key link in cancer chain
A tumor-suppressing protein snatches up an important cancer-promoting enzyme and tags it with molecules that condemn it to destruction, a research team led by scientists at The University of Texas M. D. Anderson Cancer Center reports this week in the journal Molecular Cell.
"KEAP1 is a recently discovered tumor suppressor, but how it works has not been known. IKK- is a known oncoprotein that promotes cancer in at least two different ways, but we did not know how it was regulated. We think we've answered both questions with this research," said senior author Mien-Chie Hung, Ph.D., chair and professor of M. D. Anderson's Department of Molecular and Cellular Oncology.
The researchers showed that KEAP1, short for the tongue-twisting Kelch-like ECH-associated protein 1, binds to IKK- and attaches molecules known as ubiquitins to the oncoprotein, which targets it for dissolution by the cell's proteasome complex.
They also showed that underexpression of KEAP1 is associated with poor survival among breast cancer patients, and that it's mutated and inactivated in some breast, liver, lung and colon tumors.
"KEAP1 underexpression or inactivation is involved in multiple cancers, so we are working now to identify its activation mechanism, which could lead to development of new anti-cancer drugs," Hung said. He and his colleagues also want to know whether KEAP1 works on other known oncoproteins.
Blocking overexpression of IKK-, short for IkB kinase -, is crucial for at least two reasons. Hung and colleagues have shown that the protein inhibits at least two other important tumor suppressors. More importantly, IKK- activates the NF?B (nuclear factor ?b) signaling pathway, which regulates expression of genes involved in the immune response, cellular proliferation, growth of new blood vessels, cell survival, tumor invasion, and the lethal spreading of cancer known as metastasis.