Natural Defense Protects Cells

Native pathway protects cells from cancer-causing damage
By: Sam Ohmer posted in Johns Hopkins School Newsletter Read the original article here

One of the basic principles of cell biology is that cells can respond to different conditions, both within and outside the cell. Cells have to do this to maintain homeostasis, their natural equilibrium state that corresponds to a good health for the cell.

The ability to respond to chemical insults is of particular importance because these insults often lead to cancer or other cellular problems. Chemical insults – the presence of a potentially problematic chemical – can lead to a wide range of negative effects on a cell.

An international team of cancer biologists led by Paul Talalay of the Hopkins School of Medicine recently published an analysis of the activity of one such system, a natural defense against a particularly potent type of cellular injury.

The group looked at a cancer-fighting mechanism that involves the activation of a number of proteins.

They determined that a buildup of harmful chemicals in a cell, many of which are linked to common cancers, can switch on this system through a simple and elegant pathway.

These proteins, which include glutathione-S-transferase (GST) and NADPH-quinone oxidoreductase (NQO1), are enzymes that act as antioxidants, ridding cells of a particularly dangerous class of molecules called free radicals.

A free radical is a particle with an extra, unpaired electron. This electron is highly reactive and willing to combine with just about any other chemical, so free radicals are able to damage or destroy sensitive tissues in the body, often by targeting DNA.

The genes that code for proteins like GST and NQO1 are controlled by antioxidant response elements, or AREs, which bind to the genes and activate the production of the corresponding proteins.

The problem is that free radicals are created naturally by many normal cellular functions, such as the breakdown of food for energy, as well as by exposure to environmental toxins like tobacco, drugs and alcohol.

The key is to stop this destructive process before it can spread too widely, thus increasing the chance of DNA or cellular damage. Cancer is just one of many illnesses known to be linked to free radicals. Activating AREs is a central part of the protective response.

The team worked out the chemical steps that lead to the activation of AREs. Like many biological processes, there is a natural feedback loop that has developed in this pathway.

Free radical damage causes several chemicals to accumulate in cells. These chemicals interact to activate AREs and the antioxidant response.

The team focused their efforts on NQO1, one of the two antioxidant enzymes. They performed a series of theoretical chemical analyses to determine that NQO1 is activated in two simple steps.

Both steps use reduction-oxidation or “redox” chemistry, a type of modification that involves the transfer of an electron pair between two chemicals. Oxidation refers to the gain of electrons; reduction is the loss of electrons.

In the first step, compounds called phenols are oxidized to a related chemical called quinone by the free radicals that are building up in the cell. The level of quinones floating in the cell corresponds with the amount of free radical that has been released.

In the second step, quinone oxidizes part of a protein, Keap1, that is an indirect inducer of AREs.

The oxidation of Keap1, which effectively acts as a free radical sensor, opens an opportunity for another protein to activate the ARE and transcribe the antioxidant NQO1 protein.

This pathway is elegant because it takes advantage of the natural results of free radical release, the redox class of reactions, to produce a signal the cell can understand: to produce more protein to fight these radicals.

Because the different steps in this pathway have been worked out, scientists can more effectively predict which drugs might act more effectively to induce NQO1 expression, helping cells protect themselves against free radicals and the diseases they can cause.
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