Oxygen-sensitive protein possible weapon against cancer
Researchers from Karolinska Institute present a new protein mechanism in an article in PNAS that may help to improve blood flow in a tissue in the event of low oxygen levels for example following a stroke. The hope now is that these new findings can be used conversely in the development of anti-cancer medicines.
The work on the study in question was led by Lorenz Poellinger, Professor of Molecular Biology at the Department of Cell and Molecular Biology. Together with his colleagues at Karolinska Institute and the University of Gothenburg, he has been focusing on the oxygen-sensitive protein HIF-1alfa, among others. This protein acts by regulating gene expression whereby it activates the genes that are important for the formation of new blood vessels in a tissue in the body where the oxygen supply has diminished for some reason, and to adjust the metabolism in the affected tissue to a low oxygen level. The latter is important for the ability of the tissue to survive oxygen starvation.
Following a stroke or heart disease the oxygen levels in parts of the brain and the heart decrease whereupon the function of HIF-1alfa is activated. However, low oxygen levels are measured medically even in growing cancer tumours, where the centre of the tumour mass is more and more becomes more distant to the oxygen-supplying blood vessels. One way of accessing certain tumours would therefore be to stop the mechanisms that contribute to the formation of new blood vessels.
In the recently published study, researchers have discovered that the biological response of a cell or tissue to low oxygen levels is not only controlled by the protein HIF-1alfa, but also by a new mechanism involving another protein called Filamin A. This protein is part of the 'cytoskeleton'; large filamentous proteins that provide mechanical support to the cells. Researchers found that cleavage of Filamin A into sub-fragments occurs in the event of low oxygen levels. One of these fragments is small enough to enter the nucleus, where it is physically coupled to the oxygen-sensitive gene regulatory protein. In this way, the function of this protein will be enhanced in the activation of its target genes and formation of new blood vessels.
"It will now be interesting to investigate whether it is possible to develop medicines that interfere with the interaction between the oxygen-sensitive protein and the cytoskeletal protein so as to inhibit the growth of oxygen-starved tumours," says Lorenz Poellinger.
The research was funded by the Swedish Heart and Lung Foundation, the Swedish Research Council, the Swedish Cancer Society, the Cancer Science Institute of Singapore, the Torsten Söderberg Foundation, the Ragnar Söderberg Foundation, Sahlgrenska University Hospital Foundations, the Göran Gustafsson Foundation, and the Board of Research at Karolinska Institutet.
Hypoxia-induced and calpain-dependent cleavage of filamin A regulates the hypoxic response
Xiaowei Zheng, Alex-Xianghua Zhou, Pegah Rouhi, Hidetaka Uramoto, Jan Borén, Yihai Cao, Teresa Pereira, Levent M. Akyürek & Lorenz Poellinger
PNAS Early Edition 3-7 February 2014