Energy management in cells may hold key to cancer defense

August 18, 2005

HANOVER, NH - In an ongoing effort to fight disease by manipulating energy regulation of cells, a collaborative study led by Dartmouth Medical School (DMS) has demonstrated that cells lacking a tumor-suppressing kinase called LKB1 can still maintain healthy energy levels when they become stressed. This energy regulation is essential for keeping cells from dying off too quickly. The study's results could signal new advances for combating cancerous tumor growth, but also type 2 diabetes and obesity.

The study, published in the August 12 issue of the Journal of Biological Chemistry (JBC), was headed by Dr. Lee Witters, Eugene W. Leonard 1921 Professor of Medicine and Biochemistry at DMS and of Biological Sciences at Dartmouth College, who has researched kinases for over 25 years. Kinases encompass a large family of enzyme proteins that play key roles in the workings of most animal cells. He has focused much of his research on the AMP-activated kinase (AMPK) which responsible for managing energy within cellular pathways.

"A cell's energy level is critical to its survival," explains Witters, who likens a low-energy cell to a car with no gas in its tank. "In a previous study, we found that the cellular "gas gauge," AMPK, can turn around and alter any deficits in the cell if it is turned on by the kinase LKB1. In this JBC study, we wanted to see if AMPK could also be turned on by something besides LKB1."

"We decided to work with cervical and lung cancer cells because LKB1 is absent from the cellular pathway," said Rebecca Hurley, lead author of the study and a graduate student in the Molecular and Cellular Biology Program at Dartmouth. Working closely with scientists at St. Vincent's Institute in Australia and Duke University, the DMS team concluded that two kinases in these cancer cells, CaMKKα and CaMKKβ, are able to regulate AMPK independent of LBK1.

"With the addition of these two kinases, we think we have all nearly the players responsible for energy regulation within the cell, which should offer new opportunities in cancer treatment," said Hurley. "If we can stifle a cancer cell's ability to adapt to an energy deficit, it might lose its growth advantage." "You need to know how all these proteins interact before you can make truly significant advances," echoes Witters "It's like poker; not only do you need to know what each card signifies individually, but you must have an understanding of how they play off each other in order to win."

In addition to cancer-fighting potential of AMPK regulation, the enzyme also responds to changes in insulin or glucose and mediates impaired energy metabolism, a hallmark of type 2 diabetes. "This indicates that AMPK is a very tempting target for the treatment of some forms of diabetes and even obesity," said Witters.

As Witters' laboratory continues to zero in on the central role of kinases in the treatment of disease, he acknowledges that this research is becoming more complex and multiple approaches are needed to find solutions. Witters believes that significant breakthroughs in science can only be achieved through open collaboration, citing partnerships between faculty and students, and between other institutes outside the Dartmouth community.

Often referring to his laboratory as a classroom, Witters pointed out the integral roles played by Hurley and Dartmouth College undergraduate student Jeanne Franzone '05, a co-author of the study. "Students are the grand integrators of collaboration," he said, noting that Hurley traveled to other labs in the US to complete this study. Other co-authors of the study are Kristin Anderson and Anthony Means from Duke University and Bruce Kemp from The St. Vincent's Institute and CSIRO Health Sciences and Nutrition in Australia.
-end-


The Geisel School of Medicine at Dartmouth

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