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RESEARCH BRIEFS
Regulator of Protein Degradation Emerges as Anticancer TargetIn prostate cancer, high levels of the enzyme fatty acid synthase (FASN) help tumor cells resist apoptosis and survive under less-than-optimal growth conditions. HMS researchers have identified a protease that elevates cellular FASN by blocking its degradation. The protease, which the investigators dubbed USP2a (for ubiquitin-specific protease 2a), rescues FASN by clipping off the ubiquitin tail that tags proteins for proteasomal degradation. Like FASN, USP2a is elevated in prostate cancer cells, and inactivating the protease causes degradation of the FASN protein and cell death.
Ubiquitin-specific protease 2a (USP2a) controls levels of fatty acid synthase (FASN) in prostate tumors. FASN that is normally tagged with a chain of ubiquitins (gray circles) and targeted for proteasomal degradation can be rescued by USP2a-catalyzed deubiquitination. The build-up of rescued FASN gives tumor cells a growth advantage. Blocking USP2a leads to the loss of FASN and triggers cell death by apoptosis. (Image by Jeff Cleary) "It's a new avenue for cancer drugs," said Massimo Loda, HMS associate professor of pathology at the Dana-Farber Cancer Institute and senior author of the March Cancer Cell study. "These two enzymes are of categories that are not commonly targeted by investigators. It's not your run-of-the-mill oncogene, and it's not a tumor suppressor gene. In this case, a metabolic enzyme is the target and a deubiquitinating enzyme is regulating it," he said. In previous work, Loda's group showed that FASN levels are highest in the most aggressive and deadliest prostate tumors. Other types of tumor, including breast and endometrial cancers, also have elevated FASN, and researchers know that blocking FASN kills cancer cells. In animal tests, inhibitors of fatty acid synthesis had undesirable side effects, but inhibiting FASN by shutting down USP2 may offer a solution. Regulation of protein degradation by reversible ubiquitination is likely to be a general theme in cells, and perhaps in cancer. "It's an understudied field," Loda said, noting that USP2a is only the third out of a family of more than 80 related peptidases to have its substrate identified. And one of USP2's relatives deubiquitinates and stabilizes the tumor suppressor p53, a major player in many types of cancer.
Flaws Revealed in Study Assailing MammogramsFor decades women have depended on mammograms to reveal breast tumors too tiny to be detected by touch. That trust was called into question four years ago when a pair of Danish researchers reported that their review of the clinical trial data showed that mammograms do not save lives and may even expose women to unnecessary surgical procedures. It now appears that the Danish study, which inspired controversy when it was first published, may have been deeply flawed.James Robins of HSPH and colleagues at other institutions report in the February International Journal of Epidemiology that the Danish study, which appeared in 2000, is rife with misreadings, misunderstanding, and bias. Based on their review of the study--and the clinical data on which it is based--Robins and his colleagues conclude that mammograms are, indeed, a valuable part of a woman's check-up. "The randomized clinical trial evidence that mammograms save lives from breast cancer is pretty clear," said Robins, the Mitchell L. and Robin LaFoley Dong professor of epidemiology. In their 2000 analysis, Peter Gotzsche and Ole Olsen, based in Copenhagen, focused on four clinical trials--two showing that women who had mammograms were less likely to die of breast cancer than those who did not have the procedure and two showing no difference. They dismissed the two positive studies, claiming the research did not pass a set of specified criteria. The negative studies did pass the researchers' test, however. On this basis, the Danish pair argued that the weight of evidence showed that mammograms were not beneficial. "I read the original Gotzsche and Olsen study, and I was kind of shocked," said Robins, a statistician and epidemiologist. "The rules they were using seemed very peculiar." He and his colleagues went back to the clinical data and to the Danish critique. They found that the researchers' argument was based on a combination of misreadings and misunderstandings of the clinical data and papers. In one instance, Gotzsche and Olsen ignored a critical footnote that explained a statistical feature of one of the positive studies. In another, they argued that there were inconsistencies in the way one of the positive studies reported data, but as Robins et al. discovered, the researchers had misinterpreted the data reporting rules, which were explained in the study report. Robins and his colleagues found other examples of misunderstanding and also of bias in a rebuttal by Gotzsche, which appears in the same issue of IJE. In the rebuttal, Gotzsche claims to have had no preconceived ideas about screening when he reviewed the mammography data and literature. In their rejoinder to the rebuttal, Robins and his colleagues point out that in 1997, Gotzsche published a letter in Lancet questioning the ethics of colon cancer screening studies. "Do we wish to turn the world's healthy citizens into fearful patients-to-be?" Gotzsche wrote. Having clarified the benefit of mammograms, Robins hopes that his study will get people to "concentrate on other more important issues such as who should get mammograms, how often should they get them, and the search for improved screening methods," he said. --Misia Landau
Inflammatory Pathway Uncovered with Tie to Early AtherosclerosisThe idea that atherosclerosis is at heart an inflammatory disease has been around for decades and has become widely accepted in the last few years. High cholesterol in the blood leads to activation of macrophages and starts the process of plaque formation, but so far no one knows the exact molecular structure of the proinflammatory serum lipids or the signaling pathways that immune cells use to respond.By developing knockout mice that resist getting atherosclerosis even on a high-fat diet, researchers at Massachusetts General Hospital have identified an immune signaling molecule, MyD88, as a necessary actor in the early stage of the disease. "In this study we've identified an intracellular signaling pathway involved in inflammation linked to atherosclerosis," said Mason Freeman, HMS associate professor of medicine and chief of the lipid metabolism unit at MGH. Since MyD88 transmits signals from at least a dozen cell surface receptors, the work provides a set of candidate upstream receptors that could directly or indirectly transmit the cholesterol signal. "We're not certain which of these receptors--or some other receptor nobody knows about--is important, but just having the pathway identified is a major step forward in trying to figure that out," Freeman said. The study, led by postdoctoral fellows Harry Björkbacka and Vidya Kunjathoor, appeared in April's Nature Medicine. Freeman and his colleagues started with the hypothesis that serum lipids might activate immune cells via Toll-like receptors, a family of molecules that normally recognize lipids from invading microbes. They decided to focus on MyD88, a central adaptor protein that handles the signals of all 10 Toll-like receptors and several other immune activators. After breeding MyD88-knockout mice with another strain that readily develops atherosclerosis, the researchers saw a 40 to 60 percent reduction in atherosclerotic lesions in the mice lacking MyD88. The scientists also measured a marked decrease in inflammatory-gene expression and in the number of macrophages in the artery wall. "We established that the artery wall in MyD88-null mice was not producing signals that recruit macrophages in normal mice," said Freeman. If serum lipids activate the MyD88 immune response pathway, this could explain why atherosclerosis sometimes resembles a chronic infectious disease, said Freeman. And animals infected with certain microbes are known to experience worsening of atherosclerosis in a process that could also be mediated by MyD88. --Pat McCaffrey |
