Natural Tumor Suppressor Discovered

A natural tumor suppressor that could potentially be triggered in specific cancers to prevent tumor growth has recently been discovered by scientists.

Situated on chromosome 18 and called PH domain leucine-rich repeat protein phosphatase (PHLPP, pronounced flip), researchers from the University of California, San Diego (UCSD, USA) showed that the tumor suppressor deletes a phosphate molecule, causing termination of cell-growth signaling by a protein called Akt that controls the balance between cell growth leading to tumor formation and cell death that prevents cancer.

"A drug that turns on PHLPP, so that it suppresses cell growth caused by Akt, could be a potential cancer therapy. Currently, there are no compounds identified to directly stop Akt from causing cancer growth, once Akt signaling has been initiated,” said Alexandra C. Newton, Ph.D., professor of pharmacology at UCSD.

Researchers have known that Akt is important in controlling cell growth and death, and that it is linked to some of the most common human cancers. Even though one group of researchers found a molecule called PTEN, which prevents activation of Akt, no one as yet has determined how to exactly inactivate Akt one it has been activated.

Because the Akt molecule is secured in the "on” position when it has phosphate on it, the researchers figured that there must be another molecule that will pull off the phosphate and lock Akt in the "off” position. The UCSD team did a database search for the human genome for a phosphatase, which is an enzyme that acts as a catalyst in regulating cellular processes by removing phosphate molecules. Based on the chemical components of Akt, they looked for a phosphatase linked to the PH domain, a protein module found in a large variety of chemical signaling proteins in organisms ranging from yeast to humans.

Once they found PHLPP, which they found was expressed throughout the body, the UCSD team used cellular and biochemical data in human and other mammalian tissue to establish that PHLPP levels were considerably reduced in several colon cancer and glioblastoma cell lines that had increased Akt phosphorylation. Reintroduction of PHLPP into the cell lines caused a drastic suppression of tumor growth. With further laboratory testing, the team discovered that PHLPP blocks tumor growth by deleting a certain phosphate molecule at a position called Ser473 on Akt.

The scientists observed that PHLPP's role as a tumor suppressor could be applied to all cancers where Akt is elevated, "which is a large number of cancers,” stated Dr. Newton. The study was published in the April 1, 2005, issue of the journal Molecular Cell.