A discovery led by the University of California, Irvine advances the hunt for improved treatments.
A discovery made by researchers at the University of California, Irvine about how a particular protein is activated in tumor cells may lead to more effective treatments for some of the deadliest types of cancer. The finding, which was led by scientists at the School of Biological Sciences, could potentially lead to treatment options for the particularly dangerous melanoma and pancreatic adenocarcinoma, as well as the most common type of brain cancer in children and skin cancer in adults. The study was published in the journal Life Science Alliance.
The GLI1 protein, which is essential for cell development but has also been linked to a number of cancers, was the subject of the finding. The Hedgehog signaling pathway, also known as HH, usually activates GLI1. However, scientists have known for nearly a decade that crosstalk or interaction between HH and the mitogen-activated protein kinase pathway plays a role in cancer.
“In some cases, proteins in one pathway can turn on proteins in another,” said lead author A. Jane Bardwell, a project scientist in the UCI’s Department of Developmental and Cellular Biology. “It’s a complex system. We wanted to understand the molecular mechanism that leads to GLI1 being activated by proteins in the MAPK pathway.”
GLI1 generally forms a strong bond with a protein known as SUFU. This protein inhibits GLI1, preventing it from entering the cell nuclei and turning on genes. The researchers examined seven locations on the GLI1 protein that may be phosphorylated or to which a phosphate group has been transferred.
“We identified three that can be phosphorylated and are involved in weakening the bond between GLI1 and SUFU,” said Lee Bardwell, a professor of developmental and cell biology whose lab conducted the project. “This process activates GLI1, allowing it to enter the cell nucleus, where it can cause uncontrolled growth that leads to cancer.”
He noted that phosphorylation of all three sites causes a significantly higher level of GLI1 escape from SUFU than when only one or even two phosphate groups received.
The discovery is an important step towards more effective and personalized cancer treatments. “If we can understand exactly what is going on in a particular cancer or tumor, it could be possible to develop a drug that is specific to a specific tumor or individual patient,” Bardwell said. “It would allow us to treat these diseases without the toxicity of basic chemotherapy.” In addition, many tumors of the same cancer have different mutations between individuals. Ultimately, it may be feasible to screen tumors to develop the best approach for each.
Reference: “ERK2 MAP Kinase Regulates SUFU Binding by Multisite Phosphorylation of GLI1” by A. Jane Bardwell, Beibei Wu, Kavita Y. Sarin, Marian L. Waterman, Scott X. Atwood and Lee Bardwell, July 13, 2022, Life Science Alliance.
The study was funded by the National Institute of General Medical Sciences, the National Cancer Institute, the UC Cancer Research Coordinating Committee and the Damon Runyon Cancer Research Foundation.