Cancer Research Center of Hawaii - University of Hawaii

Cancer Research Center of Hawai‘i Scientist Contributes to
Identification of a New Potential Anti-cancer Agent

Scientific Journal Nature Features Results of Study

posted: April 2008
André S. Bachmann, Ph.D., assistant professor at the Cancer Research Center of Hawai‘i, in collaboration with an international team of scientists from Switzerland, Germany, and the USA, recently worked out the structure and functional mechanism of a plant bacterium-produced molecule that may curb the growth of cancer cells. The discovery was part of the study called “A plant pathogen virulence factor inhibits the eukaryotic proteasome by a novel mechanism,” published in the April 10 issue of the scientific journal Nature.

Dr. Bachmann presented his findings at the 2008 Annual Meeting of the American Association for Cancer Research (AACR) in San Diego, April 12-16, 2008, an international conference that attracts over 17,000 cancer researchers around the world. Nature cover 2008

The study found that a molecule called Syringolin A (SylA in short) inhibits the proteasome, which is a large cellular “machine” that biodegrades regulatory proteins necessary for proper cell growth, reproduction, and cell death in animals, plants, and microorganisms. While proteasomes are abundant in normal cells, they can facilitate the cancerous state since cancer cells divide more rapidly and have undergone disruptions in their normal growth behavior. Consequently, cancer cells are more sensitive to effects of proteasome inhibitors, and adjusted drug dosages will protect normal cells while killing cancer cells.

This specificity for cancer cells gives this new and unique type of agent a distinct advantage over other types of cancer drugs and promises reduced side effects during patient treatment. Just how important the proteasome mechanism is became clear when the 2004 Nobel Prize in Chemistry was awarded to Aaron Ciechanover and Avram Hershko of Technion – Israel Institute of Technology, Haifa, Israel and Irwin Rose of the University of California, Irvine, USA for their discovery of the proteasome protein degradation pathway.

Early studies that led to this discovery were carried out in bean plants infected with a plant bacterium, Pseudomonas syringae pathovar syringae or Pss that secretes SylA and produces the brown spot disease. During the course of their work, the scientists discovered that treatment of plant leaves with SylA leads to the accumulation of those proteins that make up the proteasome machinery, and they concluded that SylA might bind the proteasome. A series of complex experiments in the test tube (called in vitro) confirmed that SylA forms an irreversible chemical bond at a specific site on the proteasomes of plants and yeast.

Armed with the exciting discovery of the structure and proteasomal binding mechanism of SylA, Dr. Bachmann needed to test whether his findings could be used to inhibit proteasomes in animal cells, specifically human cancer cells. In his experiments, the effect of SylA was tested on two different types of human tumor cells—ovarian cancer and neuroblastoma, a major form of childhood cancer. The results showed that SylA rapidly entered the cancer cells, blocked the proteasome machinery, and stopped their uncontrolled proliferation through induction of programmed cell death.

Through this research, Dr. Bachmann discovered an entirely new template/platform for the future development of novel therapeutic drugs which target a very unique pathway that is essential to the uncontrolled growth of cancer cells. The discovery is expected to have far reaching implications by providing more effective and yet safer drugs for the treatment of cancer and other diseases.

Dr. Bachmann, who is also an adjunct assistant professor at the University of Hawai‘i John A. Burns School of Medicine’s Department of Cellular Molecular Biology, assisted by his graduate student Crystal R. Archer, performed all of the laboratory testing for the cancer focus of the study. He worked with Dr. Robert Dudler and Barbara Schellenberg of the Zurich-Basel Plant Science Center, Institute of Plant Biology at the University of Zurich and Dr. Michael Groll of the Center for Integrated Protein Science, Department Chemie of the Technische Universitat Munchen. Dr. Markus Kaiser of the Chemical Genomics Centre of the Max Planck Society, Dortmund, Germany; Dr. Robert Huber of the Max-Planck-Institut für Biochemie, Martinsried, Germany; and Drs. Tracy K. Powell and Steven Lindow of the Department of Plant and Microbial Biology, University of California, Berkeley also contributed to the study.

“This is an example of true inter-disciplinary research, and our teams from the USA, Switzerland, and Germany have contributed excellent work,” said Dr. Bachmann, who is one of three corresponding authors. “I started this collaboration about three years ago with Dr. Dudler of the University of Zurich in Switzerland as part of the Cancer Research Center of Hawai‘i’s Natural Products and Cancer Biology Program focus. Our program investigates compounds found in nature, which are later synthesized by chemists so that they can become widely available in sufficient quantities for use as anti-cancer drugs.”

Dr. Bachmann added, “The next step is to conduct animal studies to evaluate the effectiveness of SylA in a live model before moving on to human clinical studies. It is my sincere hope that our discovery will fuel the interest of other scientists such that improved (proteasome inhibitor-based) drugs with lower side effects will become available in the near future in order to provide improved care and a better quality of life for cancer patients.”