Scientists have discovered that a molecule called DJ-1 is likely to be involved in the generation of human tumors through negative regulation of the well-known tumor suppressor, PTEN. The research, published in the March issue of Cancer Cell, has important implications for determining the prognosis of some human cancers, and may prove to be a suitable target for cancer therapy.
The phosphatidylinositol 3' kinase signaling pathway regulates cell growth and survival, and is inhibited by activity of the tumor suppressor PTEN. Research indicates that PTEN exerts its tumor suppressor activity by inhibiting PKB/Akt signaling that is critical for cell survival. Many human cancer cells exhibit mutations in the PTEN gene, but other cancers have the normal PTEN gene. While it is clear that without normal PTEN there is a loss of PKB/Akt inhibition that can lead to tumor growth, sometimes cancers with normal PTEN also exhibit abnormally high levels of PKB/Akt activity. In a quest to determine what molecules regulate normal PTEN, Dr. Tak W. Mak from the Ontario Cancer Institute and the University of Toronto and colleagues used a genetic screening method in fruit flies and identified the molecule DJ-1 as a PTEN suppressor.
In studies with mammalian cells, low levels of DJ-1 correlated with decreased PKB/Akt activity, while increased DJ-1 led to activation of PKB/Akt and enhanced cell survival. In cancer cells from breast cancer patients, elevated PKB/Akt activity and reduced PTEN expression were associated with elevated DJ-1levels. DJ-1 levels were increased in cells from lung cancer patients, and DJ-1 was associated with poor prognosis.
"Our results demonstrate that DJ-1 negatively regulates PTEN function, and that this cell survival control mechanism is conserved among various tissues and species. Taken together, our data suggest that overexpression of DJ-1 can modulate PTEN tumor expression to the point where oncogenesis may result from upregulated PKB/Akt-mediated cell survival," writes Dr. Mak. Elevated DJ-1 levels may explain why some tumors without PTEN mutations exhibit enhanced PKB/Akt activity.
The authors go on to suggest that DJ-1 may be a prognostic marker for cancer patients and be useful as a target for development of future cancer therapeutics. Interestingly, DJ-1 may play a role in other disease states, as it has also been recently identified as a predictive diagnostic for early-onset, autosomal recessive Parkinson's disease.
The other members of the research team include Raymond H. Kim, YingJu Jang, and Tak W. Mak of Ontario Cancer Institute and University of Toronto; Malte Peters, Carmela DeLuca, Jennifer Liepa, Lily Zhou, and Bryan Snow of Ontario Cancer Institute; Wei Shi, Richard C. Binari, and Armen S. Manoukian of University of Toronto; Melania Pintilie of Princess Margaret Hospital; Graham C. Fletcher and Mark R. Bray of Miikana Therapeutics Inc.; and Fei-Fei Liu and Ming-Sound Tsao of University of Toronto and Princess Margaret Hospital. The researchers are supported by the Canadian Cancer Society, the National Cancer Institute of Canada, Frank Fletcher Memorial Fund, David Rae Scholarship, Paul Starita Fellowship, and Canadian Institutes of Health Research.