Manipulating a Protein Called XIAP Could Lead to Tumor Cells' Death
NEW YORK (June 20, 2007) — Research led by scientists at Weill Cornell Medical College has uncovered two new potential points of vulnerability on a key cancer-promoting protein, called XIAP. Drugs that target either of these activities could help push cancer cells back into a more regular programmed cell death and thereby reduce or eliminate tumors.
These findings were published in the June 8 issue of Molecular Cell by Dr. Hao Wu, a professor in the Department of Biochemistry of Weill Cornell, and her team.
Experts know that cancers spread in two separate ways — by the uncontrolled proliferation of cells, and by their refusal to undergo normal, healthy, programmed cell death, or "apoptosis."
In many cancers, dysfunction in a biochemical cascade called the NF-kappa B pathway causes tumor cells to sidestep apoptosis and become dangerously immortal.
"So, drug development aimed at short-circuiting NF-kappa B has become very hot in the past few years," Dr. Wu says.
Her team focused on a particular protein involved in the NF-kappa B pathway called the "X-linked inhibitor of apoptosis" (XIAP). Scientists had already discovered that XIAP thwarts the apoptotic impulse by putting the brakes on key enzymes called caspases. XIAP is also known to be highly active in cancer cells, but it is found in relatively low levels in healthy cells. How XIAP inhibits caspases is known, but how XIAP induces NF-kappa B activation is entirely unclear.
"We wondered if we could find out how XIAP induces the NF-kappa B pathway," explains lead researcher Dr. Miao Lu, a postdoctoral fellow of biochemistry at Weill Cornell.
In their experiments, the researchers used a variety of cutting-edge techniques, including X-ray crystallography, to track changes in the structure and activity of XIAP and the molecules it interacts with in cells.
"We discovered that XIAP interacts with the NF-kappa B cycle in two distinct ways," Dr. Wu says.
"It interacts with another key protein, called TAB1, and it also interacts on a structural level with itself — a process called dimerization," the researcher explains.
Since both of these two activities might be vulnerable to some kind of pharmaceutical interference or interruption, they present promising new targets for the development of anti-cancer drugs.
"This is really exciting," says Dr. Wu, "because it provides two new points of attack against cancer in a pathway that pharmacological researchers are already very familiar with. It's exactly this type of basic science discoveries that we hope — one day — will help lead to a cure."
This work was funded by the U.S. National Institutes of Health.
Co-researchers include Dr. Yu-Chih Lo, Su-Chan Lin and Yihua Huang — all of Weill Cornell Medical College; Dr. Young Jun Kang and Dr. Jiahuai Han, of The Scripps Research Institute, La Jolla, Calif; and Dr. David Myszka and Rebecca Rich of the University of Utah, Salt Lake City.
Weill Cornell Medical College
Weill Cornell Medical College — Cornell University's Medical School located in New York City — is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Weill Cornell, which is a principal academic affiliate of NewYork-Presbyterian Hospital, offers an innovative curriculum that integrates the teaching of basic and clinical sciences, problem-based learning, office-based preceptorships, and primary care and doctoring courses. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research in such areas as stem cells, genetics and gene therapy, geriatrics, neuroscience, structural biology, cardiovascular medicine, AIDS, obesity, cancer, psychiatry and public health — and continue to delve ever deeper into the molecular basis of disease in an effort to unlock the mysteries behind the human body and the malfunctions that result in serious medical disorders. The Medical College — in its commitment to global health and education — has a strong presence in such places as Qatar, Tanzania, Haiti, Brazil, Salzburg and Turkey. With the historic Weill Cornell Medical College in Qatar, Cornell University is the first in the U.S. to offer a M.D. degree overseas. Weill Cornell is the birthplace of many medical advances — from the development of the Pap test for cervical cancer to the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the world's first clinical trial for gene therapy for Parkinson's disease, and, most recently, the first indication of bone marrow's critical role in tumor growth. For more information, visit www.med.cornell.edu.
Andrew Klein
ank2017@med.cornell.edu