Fatty acid enzyme levels affect lung cancer

By: Neil Neumann

Posted: 5/1/08

A recent article from Francis Kuhajda and Edward Gabrielson, both in the Department of Pathology at Hopkins Hospital, reports that inhibition of an enzyme upregulated in lung tumors may have the potential to prevent growth of those tumors.

Currently, lung cancer is the leading cause of deaths from cancer in the United States and other industrialized countries. Lung cancer, once at an advanced stage, is a nearly intractable disease with a high mortality rate after five years.

About 21 percent of the United States population smokes tobacco, exposing them to high levels of carcinogens, or compounds that cause cancer. Even those who do quit smoking are still at a high risk for developing lung cancer.

With this information, the researchers from Hopkins decided to focus on developing a drug chemopreventative agent that would prevent cancer development.

The researchers investigated a compound known as C93 and its ability to specifically inhibit an enzyme in the body known as fatty acid synthase (FAS), which is involved in the fatty acid synthesis pathway. Fatty acid synthesis is important for maintaining cellular membranes and it has been shown previously that FAS is upregulated in many cancers, although its mechanism of action remains elusive.

The researchers wanted to do two things in this study: show that FAS is upregulated in early lung tumors and test the ability of C93 to inhibit lung tumor formation in mouse models of lung cancer.

Using immunohistochemistry to look for expression of FAS, the team found that 90 percent of a specific tumor found in the lungs of smokers overexpressed FAS. This directly compares to the normal tissue found in the samples taken from lung cancer patients, which expressed no detectable levels of FAS.

Next, using carcinogens commonly found in cigarettes, the researchers induced lung cancer by exposing mice to the chemicals. They repeated the experiment and found FAS overexpression in this mouse model, allowing them to conduct research on FAS inhibitors.

Using the mouse models, the researchers treated the cancerous mice with C93, a FAS inhibitor. When given the carcinogens in conjunction with C93, the mice had a reduced number of tumors compared to untreated mice by 75 percent, a marked reduction. Also, the size of those tumors that remained decreased substantially, making this chemopreventative compound highly effective.

Although these results are promising, the researchers did not know the mechanism of action in the cells and what C93 does inside tumors to prevent their growth. Extending their analysis, the researchers found that a protein known to be upregulated in cancers was also activated in their lung tumor models in mice.

This protein is called Akt, which is a protein involved in the cellular pathways of apoptosis, or programmed cell death, and also protein synthesis. Akt is phosphorylated in its active state, and it was shown by the research group to be active in lung tumors.

Interestingly, upon treatment of the lung tumors with C93, the levels of activated Akt dropped to a remarkably low level, suggesting a strong link between FAS and Akt pathways in lung cancer.

The researchers hope to bring this drug to the clinic to prevent lung cancer before it begins. An interesting side result from the analysis of C93 is that it is non-toxic at levels used to prevent lung cancer formation.

With these results in hand, the team from Hopkins has promising results in the fight against cancer.