Energy Management In Cells May Hold Key To Cancer Defense

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

"A cell's energy level is critical to its survival," explainsWitters, 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, canturn around and alter any deficits in the cell if it is turned on bythe kinase LKB1. In this JBC study, we wanted to see if AMPK could alsobe turned on by something besides LKB1."

"We decided to work with cervical and lung cancer cells becauseLKB1 is absent from the cellular pathway," said Rebecca Hurley, leadauthor of the study and a graduate student in the Molecular andCellular Biology Program at Dartmouth. Working closely with scientistsat St. Vincent's Institute in Australia and Duke University, the DMSteam concluded that two kinases in these cancer cells, CaMKKα andCaMKKβ, are able to regulate AMPK independent of LBK1.

"With the addition of these two kinases, we think we have allnearly 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 energydeficit, it might lose its growth advantage." "You need to know how allthese proteins interact before you can make truly significantadvances," echoes Witters "It's like poker; not only do you need toknow what each card signifies individually, but you must have anunderstanding 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 mediatesimpaired energy metabolism, a hallmark of type 2 diabetes. "Thisindicates that AMPK is a very tempting target for the treatment of someforms of diabetes and even obesity," said Witters.

As Witters' laboratory continues to zero in on the central roleof kinases in the treatment of disease, he acknowledges that thisresearch is becoming more complex and multiple approaches are needed tofind solutions. Witters believes that significant breakthroughs inscience can only be achieved through open collaboration, citingpartnerships between faculty and students, and between other institutesoutside the Dartmouth community.

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