Proliferation protein goes rogue in lung cancer

Rac1b could be treatment target

Web edition : 3:08 pm

A defective protein might be a key go-between in the string of terrible molecular events that lead to lung cancer. The protein, called Rac1b, gets activated by other compounds and launches cells in smokers? lungs toward malignant behavior, experiments in human cells and mice suggest.

The findings open the door for lung cancer researchers to investigate the molecular chain reaction, or pathway, in which Rac1b is involved. Since Rac1b seems to show up early in lung cancer, it might also make a target for diagnosis or early-stage treatment, researchers report in the July 11 Science Translational Medicine.

?This is really comprehensive work,? says Farrah Kheradmand, a pulmonologist at Baylor College of Medicine in Houston, who wasn?t part of the study team. ?This gives us ammunition to go after Rac1b, an inconspicuous molecule, to try to inhibit it.?

Rac1b is a variant of Rac1, a protein involved in cell proliferation. But while the gene that encodes Rac1 routinely turns itself off after producing its protein, the variant gene making Rac1b doesn?t. ?It?s not meant to be on all the time,? says study coauthor Derek Radisky, a cell biologist at the Mayo Clinic in Jacksonville, Fla. So the aberrant version of the protein gets made in excess.

Because earlier work hinted that Rac1b might play a role in some cancers, Radisky and his colleagues examined lung tissue from smokers with lung cancer and found far higher concentrations of the rogue protein in cancer cells than in nearby noncancerous cells.

Tests in mice revealed that Rac1b gets activated by an enzyme called MMP3, which is involved in the breakdown and rebuilding of tissues such as collagen and elastin. These strong connective tissues hold organs and other body parts in place.

The mouse experiments indicated that MMP3 activation of Rac1b triggers another process by which lung-lining cells called epithelial cells abandon their posts and change behavior. While the process helps in wound healing ? when cells are called upon to take on emergency roles ? it has also been linked to cancer. Some work suggests it is a way for tumors to create space for themselves, Radisky says.

But the process, especially when it involves Rac1b, still remains hazy. For instance, it?s not clear how MMPs activate Rac1b, he says. Nevertheless, says Sandra McAllister, a cancer biologist at Harvard Medical School, Rac1b does help to fill in one of the gaps in the understanding of lung cancer progression. ?It seems to be adding a function beyond the normal Rac1 protein,? she says, ?turning epithelial cells in this context into cancer cells.?

According to the American Cancer Society, smoking accounts for 80 percent of lung cancer deaths. Carcinogens from tobacco smoke are known to cause mutations in lung cells that limit their ability to stop dividing. McAllister hypothesizes that smoke hitting lung cells could draw attention in the same way a wound would, triggering a signal to heal. ?That might be part of a normal process,? she says, ?but it?s an unregulated process here, and Rac1b might be at the heart of that.?

Found in: Biomedicine and Body & Brain

Source: http://www.sciencenews.org/view/generic/id/342207/title/Proliferation_protein_goes_rogue_in_lung_cancer

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