Gene Enables Cells To Survive Even If Growth Stops

Date: Feb-18-2013Researchers in Australia have discovered a genetic defect that can stop cells growing but forces them into a death-defying state where
they consume their own cellular material to survive. They believe the discovery of such an important feature of cell growth could lead to new treatments for diseases, including cancer.

Joan Heath, Associate Professor the Melbourne-Parkville Branch of the Ludwig Institute for Cancer Research, and colleagues, write about their
findings in the 7 February online issue of PLOS Genetics.

Heath, a Ludwig Institute Member, has recently transferred her research group to the Walter and Eliza Hall Institute.
Studying Zebrafish Embryos
Heath and her team were studying zebrafish embryos when they made their discovery. The embryos they were examining contained genetic
mutations that stop cells growing rapidly during organ development.

They chose to study zebrafish embryos because, as she explains in a press statement:

"Zebrafish embryos provide us with a great laboratory model for these studies because they are transparent, an attribute that allows us to track
the growth of rapidly developing organs in live animals under a simple microscope."

Another reason, she adds, is that the "genes controlling growth and proliferation of developing tissues are essentially identical in zebrafish and
humans, and are known to be frequently commandeered by cancer cells."
Blocking Ribosome Production
The researchers discovered that a variant of a little-known gene called pwp2h, causes ribosomes to assembly incorrectly.

Ribosomes are "protein factories": large molecular machines inside cells that make the proteins essential for cellul growth and division. If they
don't assemble properly, protein manufacture stops, and cells stop dividing.

Researchers are currently very interested in developing therapies that target ribosome production as a way to stop cancer cells dividing.

But what intrigued Heath and her colleagues was the fact that, as she explains, "cells under stress from ribosome failure did not die. Instead, the
cells switched on a survival mechanism called autophagy and began obtaining nutrients by digesting their own intracellular components."
Implications for Cancer Treatment
Heath says their discovery could be important for researchers looking into cancer treatments that target ribosome production.

Their study suggests treatments that disrupt ribosome assembly would have the desired effect of stopping cell growth, but they could also have the
undesired effect of pushing the cells into a survival state.

"An anti-cancer treatment that inadvertently promotes the survival of cancer cells through autophagy is clearly not desirable," says
Heath.

But, she and her colleagues also discovered a way around this:

"... our findings in zebrafish show that if ribosome assembly is blocked and, at the same time, autophagy is inhibited, cells die rapidly."

The researchers suggest perhaps a combination of inhibitors would be an effective treatment for cancer: one blocking ribosome production, and
the other blocking cell autophagy.

The team plans to continue with the zebrafish work. They have identified a number of cell processes that rapidly dividing cells like cancer
cells rely on. Their next step will be to test whether these are suitable targets for anti-cancer drugs.

Funds from the National Health and Medical Research Council and the Victorian Government helped finance the study.

Written by Catharine Paddock PhD

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