UQ collaboration identifies new link between cancer and cholesterol
Two University of Queensland groups have combined forces to identify a vital new link between the changes which lead to cancer and the regulation of cholesterol in cells.
The new findings, published as the cover article of the June issue of the prestigious journal Nature Cell Biology, have centered on a family of proteins called caveolins.
"The study improves our knowledge of basic cell biology and some of the factors that might lead to cells growing out of control in cancer," researcher Dr Rob Parton said.
Researchers in Dr Parton's laboratory (Centre for Microscopy and Microanalysis, Centre for Molecular and Cellular Biology and Department of Physiology and Pharmacology) prepared modified caveolin proteins and showed that these proteins were able to stop infection of cells by certain viruses, which normally cause tumour formation.
They then teamed up with Professor John Hancock in the Queensland Cancer Fund Laboratory of Experimental Oncology, Department of Pathology, an expert in molecular oncology, to test the effects of the mutant caveolin proteins on the function of Ras proteins.
Ras proteins are crucial controllers of cell replication. If the controllers go wrong, this can result in cancer. In fact, mutations in Ras occur in many human tumours including 90 percent of pancreatic cancers, 50 percent of colon cancers, and 30 percent of acute leukaemias.
The collaborative studies, funded by National Health and Medical Research Council (NHMRC) and the Royal Children's Hospital Foundation, showed that the mutant caveolin proteins completely blocked the activity of one type of Ras protein. They then set out to try to find out how the caveolin mutants could block the activity of the Ras proteins. Intriguingly, they showed that the caveolin mutants were affecting how cells handle cholesterol.
"These results change the way that we think about how cholesterol works in cells and its relationship to cell replication," Dr Parton said.
"We speculate that cholesterol plays a vistal role in organising proteins at the surface of cells."
Dr Parton said they suggested that Ras proteins must associate with these cholesterol-rich areas of the membrane in order to work to control cell replication. In addition, the results suggest that the major function of caveolins might be to control how cholesterol is transported around in the cell and particularly how it is delivered to the areas containing Ras proteins.
"The findings have important implications for understanding the changes which occur in cells when they become cancerous as well as for understanding how viruses enter cells," he said.
"They also highlight an unexpected role of cholesterol in cell organisation. Since several human diseases are associated with defective cholesterol transport, the findings may also have implications for understanding the long-term effects of cholesterol trafficking defects. For example, in Niemann Pick type C disease, which is associated with fatal neurological defects, there is abnormal accumulation of cholesterol within cells."
In a second paper in the June issue of Nature Cell Biology, Parton and their Swiss collaborators headed by Professor Jean Gruenberg of the University of Geneva, have identified the intracellular site where cholesterol accumulates in the cells of patients with Niemann Pick type C disease.
In a study funded by grants from the NHMRC and a project grant from the Human Frontier Science Program, they then go on to show that these cells cannot transport proteins normally because of the abnormal cholesterol levels.
Dr Parton is now studying the relationship between this disease and caveolin in collaboration with a Niemann-Pick disease expert, Associate Professor Jean Wilson of the University of Arizona (Tucson) who is presently a sabbatical visitor in the Parton laboratory.
Researchers involved in the projects include PhD student Sandrine Roy, research assistant Robert Luetterforst and Dr Toshi Kobayashi of the University of Geneva.
For further information, contact Dr Parton, telephone 07 3365 6468.
