A study from Princess Margaret Cancer Centre has identified a new potential biomarker and therapeutic target for lung and other cancers.
This biomarker is the enzyme Nek10, a member of a family of proteins implicated in aspects of DNA damage response, cell division and signalling.
"Previously, our lab found important roles for Nek10 in regulating the cell cycle in response to UV damage," says
Dr. Vuk Stambolic, Senior Scientist at the Princess Margaret and senior author of the study. "Additionally, we noticed high levels of this protein in the lung and found that in lung cancer cells, it plays a key role in modulating p53, an important protein for protecting genome integrity."
While it is known that cancer cells frequently exhibit disruptions in cell cycle regulation and cell death, the specific involvement of Nek10 in these processes remains predominantly unexplored.
"We found that a deletion of Nek10 in lung cancer cells showed a significant elevation in levels of a protein called β-catenin," says Dr. Previn Dutt, scientific associate at the Princess Margaret and first author of the study. "This observation was particularly noteworthy due to the critical role of β-catenin in cell fate determination, regulating the stem cell population, and cell adhesion during development and tissue maintenance.
"Dysregulation of β-catenin can contribute to the development of diseases and has been shown to impact a variety of cancers."
The team then sought to understand Nek10's role in regulating β-catenin levels as this could provide valuable knowledge on how these proteins interact to impact cancer cells.
Through a series of molecular experiments conducted on lung cancer cells, the study demonstrated that Nek10 directly modifies β-catenin at a specific site, and that this modification – called phosphorylation – prevents its abnormal accumulation.
"Subsequent results indicated that the absence of Nek10's phosphorylation of β-catenin hinders its interactions with proteins responsible for its degradation," adds Dr. Dutt.
Researchers further elucidated the impact of Nek10 loss in cells and tissues through assays aimed at assessing their tumour-forming ability. They found that when Nek10 was deleted, there was a reduced ability of cells to grow, invade and spread.
"Targeting the Nek10 pathway presents a potential avenue for regulating β-catenin levels and thereby influencing cancer progression," concludes Dr. Stambolic, who is also a professor in the Department of Medical Biophysics at the University of Toronto.
"This discovery is significant because it identifies a previously unrecognized function for Nek10, suggesting its potential as both a prognostic marker and therapeutic target in various cancers, including lung cancer."
This work was supported by the Canadian Institutes of Health Research and The Princess Margaret Cancer Foundation.
