While the top layers of skin cells will replace themselves a thousand times over the course of a person’s lifetime, other cells in the body do not divide at all. To help prevent abnormal cell growth, there are strong brakes in-place to prevent division.
“There is a lock on cells that prevents tumorigenesis by keeping cells from just erroneously going into ‘S phase,’ or the DNA replication phase, and starting cell division,” said UNC Lineberger’s Michael J. Emanuele, PhD, an assistant professor in the UNC School of Medicine Department of Pharmacology. “Here, we show how a common growth signaling pathway in cells can destroy one of the brakes on cell division to allow cell division to move forward.”
In the study, researchers described how a common signaling pathway that’s turned on in cancer to urge cells to divide – the PI3-kinase signaling pathway – helps to turn off one of the natural brakes on cell division. Specifically, PI3-kinase signals activate the AKT enzyme, which passes a series of messages like the game of “Telephone” to tell cells to move forward with division. AKT binds to another molecule, called Cyclin F, to allow it destroy the cdh1 molecule, which releases a “brake” on cell division that is controlled by a large, multi-subunit enzyme termed the Anaphase Promoting Complex/Cyclosome, or APC/C.
Emanuele said cancer cells could hijack this naturally occurring pathway to release the brakes on division.
“The cancer cell is leveraging a normally functioning pathway in the cell, but aberrantly turning it on, taking advantage of something built into the circuitry of the cell to allow cell division to occur to promote tumor proliferation,” he said.
Their findings could lead to a potential new area of cancer drug discovery. Blocking Cyclin F could potentially prevent the degradation of cdh1, and keep the APC/C “brake” on cell division in place. Emanuele said they believe this strategy could be less toxic than other strategies to prevent cell division.
In addition to Emanuele, other authors include Rajarshi Choudhury, Thomas Bonacci, Xianxi Wang, Andrew Truong, Anthony Arceci, Yangqiong Zhang, Christine A. Mills, Jennifer L. Kernan, and Pengda Liu.
The study was supported by the Natural Science Foundation of China, the National Institutes of Health and the Intramural Research Program of the National Institute of Environmental Health Science.