Purdue News

April 5, 2005

Genetic testing could bolster radiotherapy's effectiveness against cancer

WEST LAFAYETTE, Ind. – Obtaining a genetic picture of how a tumor will react to the many treatment techniques available could help doctors prescribe therapies customized for individual cancer patients' needs, suggests a Purdue University research team.

A group of scientists including Jian-Jian "J.J." Li has found a trio of proteins often present in cancer cells that protect the tumor from destruction by radiotherapy. Because no single protein in the group is responsible for keeping the cancer alive, Li said that the key to a successful assault could rest in a deeper understanding of the relationship among these protein molecules – an understanding that could be made available through genetic testing.

"We have discovered that breast cancer cells defend themselves on the molecular level against radiation, and this response could be reducing the effectiveness of modern medicine's fight against cancer," said Li, who is an associate professor of health sciences in Purdue's School of Health Sciences. "Because these three proteins interact in ways peculiar to each tumor, it might help doctors to first obtain the 'genetic fingerprint' of cancerous tissue in order to find out which treatment method will be most effective."

The research appears in this week's issue of the Journal of Biochemistry. Li's co-authors include researchers from the City of Hope National Medical Center, Bio-Rad Laboratories and the National Institutes of Health.

All living cells are kept alive through the efforts of thousands of different proteins, each of which may have many different and interrelated functions. Proteins are brought into action, or "expressed," by genes in the cell's DNA when certain needs arise – such as reproduction or metabolizing energy. Three such proteins found in most human cells have been the focus of Li's research for several years, each of which is commonly known to scientists by a technical name: ERK, NF-kappa B and GADD45 beta.

"In healthy cells, these three proteins all play a role in building new cellular structures, allowing the body to grow and regenerate," Li said. "Each has individual functions that are well known. NF-kappa B and ERK, for example, work as construction managers that tell the genes where more building blocks are needed and how they should be arranged, while GADD45 beta helps repair damage to DNA. This helps keep a cell from mutating as it grows."

NF-kappa B beta is known to be present in abnormally high amounts in tumors. However, scientists also have noticed that after the NF-kappa B has been inhibited, the cancer cells are less responsive to radiotherapy. Apparently, Li said, the presence of the protein keeps tumor cells alive despite receiving a punishing amount of radiation that ordinarily would kill them.

"Previous research has also implicated NF-kappa B in this type of radioresistance to cancer," Li said. "No one really knew what was happening. But the issue needed resolution because, once again, we were confronting the standard dilemma in cancer treatment: How do you destroy the cancer without damaging the surrounding healthy cells?"

Li's group found that it was not just one of these proteins that was fighting hard to save the cells – it was all three. After subjecting breast cancer cells in the lab to the stress of ionizing radiation, the group found that the proteins all are co-activated in a pattern of mutual dependence, coordinating among themselves to increase cell survival rate.

"The essence of our discovery can expressed rather simply," Li said. "Genes in the body do not operate in isolation, but as a team. This is the sort of lesson we will probably learn again and again as the recently decoded human genome reveals more of its secrets."

Indeed, it could be in the genome that a solution to the dilemma will be found, Li said.

"If we can test cancer cells not for just three proteins but for thousands, the 'genetic fingerprint' such a test would provide might help us to devise better therapies to kill tumors," he said. "Knowing in general that proteins A, B and C are defending the cell may allow us to administer drugs that block them, which could allow us to irradiate the now-defenseless cancer with lower radiation levels. This would be simultaneously more effective against the cancer and less harmful to the patient in general."

In the case of breast cancer cells, the proteins in question are ERK, NF-kappa B and GADD45 beta. But Li said that this was probably the first of many discoveries that relate proteins to one another in such a fashion.

"These three proteins are most likely the tip of the iceberg," Li said. "This discovery is all about interaction, which goes beyond any one protein or gene expression. People used to think NF-kappa B was just a gene regulator. Now we realize it could be part of a signaling network that decides the pattern of gene expression – a pattern that remains mysterious."

This research was funded in part by the National Institutes of Health's National Cancer Institute and the Department of Energy.

Li is associated with the Purdue Cancer Center. One of just eight National Cancer Institute-designated basic-research facilities in the United States, the center attempts to help cancer patients by identifying new molecular targets and designing future agents and drugs for effectively detecting and treating cancer.

Writer: Chad Boutin, (765) 494-2081, cboutin@purdue.edu

Source: Jian-Jian Li, jjli@purdue.edu

Purdue News Service: (765) 494-2096; purduenews@purdue.edu



Co-activation of ERK, NF-kappa B, and GADD45ß
in Cell Response to Ionizing Radiation

Tieli Wang, Yu-Chang Hu, Shaozhong Dong, Ming Fan,
Daniel Tamae, Munetaka Ozeki,
Qian Gao, David Gius, and Jian-Jian Li

NF-kappa B, an early stress response transcription factor, has been well-documented to play an active role in signaling cell stress responses. GADD45ß, a primary cell cycle element responsive to NF-kappa B activation, functions as an antiapoptotic protein. The extracellular-signal regulated kinase (ERK) coordinates the regulation of cell proliferation and survival. The present study provides evidence demonstrating that NK-kappa B, ERK and GADD45ß are co-activated by ionizing radiation (IR) in a pattern of mutually dependence and coordinate to increase cell survival. Stress conditions generated in human breast cancer MCF-7 cells by the administration of a single dose of 5 Gy resulted in the activation of ERK, along with an enhancement of the NF-kappa B transactivation and GADD45ß expression. Overexpression of dominant negative Erk (DN-Erk) or pre-exposure to ERK inhibitor PD98059 inhibited NF- kappa B activation. Transfection of dominant negative mutant I kappa B that blocks NF- kappa B nuclear translocation, inhibited ERK and GADD45ß and increased cell radiosensitivity. NF-kappa B and ERK were inhibited by transfection and antisense GADD45ß, and interaction of p65 and ERK was detected in MCF-7 cells by bimolecular fluorescence complementation analysis. Overall, these results demonstrate a possibility that NF-kappa B, ERK and GADD45ß are coordinated in a loop-like signaling network that functions to increase cell survival under the stress of ionizing radiation.


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