SCIENTISTS REVEAL UNANTICIPATED ROLE FOR INTRACELLULAR IRON REGULATION IN AN APOPTOTIC PATHWAY
UMass Medical School research has relevance to study of chronic myelogenous leukemia and its treatment
January 01, 2006
Worcester, MA - Cancer researchers have long speculated about the deeper role iron metabolism plays in tumor cell biology. Now, a recently published study from scientists of the Howard Hughes Medical Institute and the University of Massachusetts Medical School links iron metabolism with cell death and mechanisms of cellular transformation in leukemia with significant implications for an understanding of the relationships between iron and gene expression and cancer progression.
In the Dec. 29, 2005 issue of Cell, Howard Hughes Medical Institute Investigator Michael R. Green, MD, PhD, the Lambi and Sarah Adams Chair in Genetic Research and professor of molecular medicine and biochemistry & molecular pharmacology at the University of Massachusetts Medical School, and colleagues describe the relationship between protein 24p3, its newly identified receptor and their surprising involvement in a molecular mechanism that contributes to chronic myelogenous leukemia.
Broadly interested in how genes are expressed in eukaryotic cells, the mechanisms involved and the relevance of those mechanisms to normal physiological and disease states, Dr. Green has concentrated much of his research efforts on the role of transcriptional regulation (the first step of gene expression) in apoptosis, or programmed cell death. The study of apoptosis has a particular relevance to cancer research because cancer cells have built-in mechanisms that prevent normal programmed cell death, allowing for the proliferation of cancer cells.
Building on the premise that transcriptional regulation would activate genes that would then lead to a pathway of programmed cell death, Green and colleagues have sought to identify these pro-apoptotic genes. In earlier research, published in Science in 2001, their lab identified a transcriptional regulation step in the programmed death of cells that were dependent on interleukin 3, a growth factor. The researchers found that when interleukin 3 was withdrawn from the cells, a gene called 24p3 was activated and its protein product secreted outside of the cell, before it was received back into the cell through a then unidentified receptor, leading to apoptosis.
In this current research, these scientists have not only identified the receptor for 24p3, but also-expanding upon the knowledge that 24p3 had been previously identified as an iron-binding protein-determined that 24p3 and its receptor mediate a rapid loss of iron from the cell leading to its death.
"After identifying the receptor, we began to study the mechanism by which it was able to deliver iron and mediate cell death. Interestingly, we found that this single receptor could do both and it was entirely dependent upon the iron content of 24p3," Green explained. "If we took 24p3 and loaded it with iron, it delivered it to the cell and the cell was happy and proliferated. If the 24p3 lacked iron, it would still be taken up by the receptor, but would chelate iron from the cell, lowering the iron content, ultimately leading to cell death."
This surprising finding has particular implications in cancer research. Because it is known that iron is required for cellular proliferation and that the sufficient depletion of iron can lead to apoptosis, iron chelators are a prime area of research in cancer treatment. Such iron chelators safely bind iron and are excreted without further interaction with the body. Cancer cells in particular are sensitive to iron concentration making these chelators a promising area of study.
In addition to the identification of the 24p3 receptor and its relationship to iron metabolism, Green and colleagues also examined the relationship of BCR-ABL, a protein with oncogenic properties that contributes to the progression of chronic myelogenous leukemia. As has been established, the withdrawal of interleukin 3 from dependent cells leads to apoptosis. However, researchers had also established that the introduction of certain proteins, like BCR-ABL, could render the cells independent from the need for this cytokine and therefore resistant to cell death. Building upon the 2001 study, when Green's lab found that 24p3 was activated upon the withdraw of interleukin 3 leading to cell death; the scientists supposed that BCR-ABL must interfere with the pathway. They speculated that this interference occurred in the simplest way; BCR-ABL prevented 24p3 from being transcriptionally activated. However, the simplest explanation was disproved. The researchers actually found that the opposite was true.
"In fact, what BCR-ABL does is allow for 24p3 to be essentially activated all the time, which raised the question 'why aren't the cells dead,'" Green said. "Interestingly, we found that the reason the cells were not dead is because BCR-ABL also turns the 24p3 receptor down. Now the cells, while producing enough 24p3 to kill their normal neighbors, can't take in 24p3, rendering them resistant to cell death."
This remarkable finding has implications for the understanding and treatment of leukemia and lends greater understanding to the effectiveness of a leukemia drug currently on the market. Novartis AG's chronic myeloid leukemia drug Gleevec (imatinib) blocks BCR-ABL activity. In this research, Green and colleagues demonstrated that Gleevec increased the expression of the 24p3 receptor in cells expressing the BCR-ABL, removing the protection afforded by the protein and rendering the cells susceptive to 24p3's apoptotic effects.
"While we understood that Gleevec targeted BCR-ABL, it wasn't clear how it was killing the cells. We now believe that this 24p3 pathway contributes to the way that this drug works, which may have further applications in the study of acquired Gleevec resistance," Green said.
Going forward with the information gained from this research, Green and colleagues are currently working on determining whether other oncogenic tyrosine kinases, like BCR-ABL, can alter the expression of 24p3 and its receptor.
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