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A new discovery in how a certain protein is activated in tumor cells could lead to better treatments for some of the deadliest forms of cancer, researchers report.
The discovery could eventually lead to potential treatments for the most common types of especially dangerous melanoma and pancreatic adenocarcinoma, as well as childhood brain cancer and adult skin cancer.
The study appears in the journal Life Science Alliance,
The finding relates to the GLI1 protein, which is important in cell development but has also been found in various cancers. GLI1 is normally activated by the Hedgehog signaling pathway, known as HH. However, scientists have known for nearly a decade that the crosstalk, or interaction, between Hh and the mitogen-activated protein kinase pathway has a role in cancer.
“In some cases, proteins in one pathway can turn on proteins in another,” said lead author A. Jane Bardwell, project scientist in the Department of Developmental and Cell Biology at the University of California, Irvine.
“It’s a complex system. We wanted to understand the molecular mechanism that activates GLI1 by proteins in the MAPK pathway.”
GLI1 normally binds tightly to a protein called SUFU. That protein suppresses GLI1, preventing it from entering the cell nucleus and turning on the gene. The scientists examined seven sites on the GLI1 protein that can be phosphorylated, or have a phosphate group transferred to it.
“We have identified three that can be phosphorylated and are involved in the weakening of the binding between GLI1 and SUFU,” says Lee Bardwell, a professor of development and cell biology. whose lab conducted the project. “This process activates GLI1, enabling it to enter the nucleus of cells, where it can cause uncontrolled growth that can result in cancer.”
They noted that due to the phosphorylation of all three sites, SUFU escapes significantly higher levels of GLI1 than if only one or two of them received phosphate groups.
This discovery is an important step towards more effective and personalized cancer treatment.
“If we can understand what’s happening in a certain cancer or in a particular tumor, it may be possible to develop a drug specific to a specific tumor or individual patient,” Bardwell says. “This will allow us to treat these diseases without the toxicity of basic chemotherapy.”
In addition, multiple tumor individuals with the same cancer have different mutations. Eventually, it may be possible to examine the tumor in order to develop the best approach for each.
Additional co-authors are from Stanford University and UC Irvine.
The National Institute of General Medical Sciences, the National Cancer Institute, the UC Cancer Research Coordinating Committee and the Damon Runyon Cancer Research Foundation funded the work.
Source: UC Irvine