Lung cancer cells' survival gene seen as drug target

One of the deadliest forms of cancer appears to carry a specific weakness. When a key gene called 14-3-3zeta is silenced, lung cancer cells can't survive on their own, researchers have found.

The gene is a potential target for selective anti-cancer drugs, says Haian Fu, PhD, professor of pharmacology, hematology & oncology at Emory University School of Medicine and Emory Winship Cancer Institute.

The research results will be published the week of Dec. 24 in the Proceedings of the National Academy of Sciences. The paper's first author is Zenggang Li, PhD, a postdoctoral fellow in Dr. Fu's laboratory.

Lung cancer kills more Americans annually than any other type of malignancy, according to the National Cancer Institute. Yet treatment options are very limited, Dr. Fu says.

"The recent trend towards targeted therapies requires us to understand the altered signaling pathways in the cell that allow cancer to develop," he says. "If you think about genes that are dysregulated in cancer as drivers or passengers, we want to find the drivers and then, aim for these drivers during drug discovery."

Dr. Fu and his collaborator, Fadlo Khuri, MD, deputy director of clinical and translational research at Emory Winship Cancer Institute, chose to focus on the gene 14-3-3zeta because it is activated in many lung tumors. In addition, recent research elsewhere shows that survival of lung cancer patients is worse if the gene is on overdrive in their tumors, Dr. Fu says.

14-3-3 genes are found in mammals, plants and fungi. In the human body, they come in seven flavors, each given a Greek letter. Scientists describe the proteins they encode as adaptors that clamp onto other proteins. The clamping function depends on whether the target protein is phosphorylated, a chemical switch that regulates processes such as cell division, growth, or death.

"We knew that 14-3-3 is important in controlling EGFR (epidermal growth factor receptor) signaling, which is a main pathway driving lung cancer," Dr. Fu says. A couple of recently introduced drugs that were shown to be effective against lung cancer target EGFR, he adds.

In the PNAS study, the authors used a technique called RNA interference to selectively silence the 14-3-3zeta gene. They found that when 14-3-3zeta is turned off, lung cancer cells become less able to form new tumor colonies in a laboratory test.

One of the most important properties of cancer cells is their ability to grow and survive without touching other cells or the polymers that connect them. While the authors found that the cells with 14-3-3zeta turned off do not grow more slowly, the cells are vulnerable to anoikis (Greek for homelessness), a form of cell death that happens when non-cancerous cells that are accustomed to growing in layers find themselves alone.

Further experiments showed that 14-3-3zeta regulates a set of proteins called the Bcl2 family that control programmed cell death, and its absence upsets the balance within the family.

"You can see how control of anoikis means 14-3-3zeta could play a critical role in cancer invasion and metastasis," Dr. Fu says. "The mechanistic question we still haven't answered is: what makes zeta unique so that it can't be replaced by the others."

The finding has implications beyond lung cancer, in that 14-3-3zeta is also activated in other forms of cancer such as breast and oral, he notes.

"Dr. Fu and his team's findings unmask the role of 14-3-3 zeta in the survival advantage of lung cancer cells and their dependence on it," Dr. Khuri says. "Targeting this critical molecule could lead to meaningful therapeutic progress."

Since 14-3-3zeta was identified as a promising target for drugs, Dr. Fu and his co-workers are making use of a robot-driven screening program at the Emory Chemical Biology Discovery Center to sort through thousands of chemicals that may disrupt its interactions specifically.

They hope to identify these compounds rapidly and move them from bench into clinic testing to benefit patients.

Source: Emory University

Related stories:

Smoking and solid fuel use in homes in China projected to cause millions of deaths
If current levels of smoking and biomass and coal fuel use in homes continues, between 2003 and 2033 there will be an estimated 65 million deaths from chronic obstructive pulmonary disease (COPD) and 18 million deaths from lung cancer in China, accounting for 19% and 5% of all deaths in that country during this period.
Probing Question: Could your kitchen counters be radioactive?
Verde Butterfly. Black Galaxy. Kashmir Gold. If you’ve remodeled your kitchen in the last decade, chances are you encountered one of the 1,600 varieties of granite imported into the United States from 64 different countries. According to recent market research, demand for natural stone countertops has increased 5 percent annually between 2001 and 2006, with granite being the most popular option. And why not? Granite is not only durable, resistant to mold and mildew, and easy to clean, but because no two pieces of granite are alike, your counter will have its own unique look.
Liver transplant recipients almost 3 times more likely to develop cancer
Cancer incidence is higher among liver transplant recipients in Finland compared to the general population, according to a new study in the October issue of Liver Transplantation.
Scientists warn US Congress of cancer risk for cell phone use
The potential link between mobile telephones and brain cancer could be similar to the link between lung cancer and smoking -- something tobacco companies took 50 years to recognize, US scientists warned Thursday.
Social class dictates cancer risk
Cervical and lung cancer are more common in poor people while rates of breast cancer and melanoma are higher in the wealthy. A detailed analysis of the incidence of these four different kinds of cancer, carried out on more than 300,000 English cancer patients and published today in the open access journal BMC Cancer, describes the effects of socioeconomic group, region and age.
Scientists identify novel inhibitor of human microRNA
Scientists at The Wistar Institute and their colleagues have identified, for the first time, a molecule that can regulate microRNAs – short strands of RNA that play a vital role in gene expression and are closely associated with cancer. The discovery points the way to the development of a new generation of cancer drugs.
Racial disparities decline for cancer in Missouri
Cancer death rates in the United States are highest among African Americans, but a new report shows that in Missouri the disparity in cancer incidence and death between African Americans and whites is declining. As a result, cancer incidence (the rate of newly diagnosed cases) between the races is equal, although the death rate will probably remain higher for African Americans for some time.
Physicians often miss opportunities to show empathy
In consultations with patients with lung cancer, physicians rarely responded empathically to the concerns of the patients about mortality, symptoms or treatment options, according to a study led by a University of Rochester Medical Center researcher.

News discussion:

Medicine & Health news