Manipulating XIAP Protein May Lead to Tumor Cell Death

Drugs that target either of these activities could help force cancer cells back into a more regular programmed cell death and thereby reduce or eliminate tumors.

These findings were published in the June 8, 2007, issue of the journal Molecular Cell by Dr. Hao Wu, a professor in the department of biochemistry of Weill Cornell Medical College (New York, NY, USA), and her team.

Specialists know that tumors metastasizes in two separate ways--by the uncontrolled proliferation of cells, and by their refusal to undergo normal, healthy, programmed cell death, a process called apoptosis. In many tumors, dysfunction in a biochemical cascade called the nuclear factor- (NF)-kappa B pathway causes tumor cells to avoid 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 stated.

Dr. Wu's team focused on a specific 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 very active in cancer cells, but it is found in comparatively low levels in healthy cells. How XIAP suppresses caspases is known, but how XIAP triggers NF-kappa B activation is not yet known.

"We wondered if we could find out how XIAP induces the NF-kappa B pathway,” explained lead researcher Dr. Miao Lu, a postdoctoral fellow of biochemistry at Weill Cornell.

In their experiments, the researchers utilized a variety of cutting-edge techniques, including x-ray crystallography, to monitor 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 said. "It interacts with another key protein, called TAB1, and it also interacts on a structural level with itself--a process called dimerization.”

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,” remarked 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.”


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