Our latest paper is now freely available online as a fully formatted pdf from the Journal of Experimental and Clinical Cancer Research. As I have promised, here is a non-technical summary!
What did we study?
This work is about malignant mesothelioma, an unusual type of cancer that is caused by asbestos. It is always deadly, and current treatment extends life expectancy only by a few months. We have been working for some time on a new experimental drug called selenite – a simple, selenium-based compound.
Interestingly, mesothelioma cells come in two kinds – epithelioid and sarcomatoid. If a tumor contains sarcomatoid cells, the patient will be expected to respond worse to therapy and die sooner. We have previously found that selenite is particularly effective against sarcomatoid cells, and that it is able to induce apoptosis, the “suicide program” of the cancer cells.
In this paper, we studied the apoptosis mechanisms in both epithelioid and sarcomatoid cells, to see if there were any differences that could explain why sarcomatoid cells are more sensitive. Also, very little was known about the apoptotic response to selenite in mesothelioma cells, we wanted to see how they compare to other cells.
What did we find?
Selenite caused the activation of a number of apoptosis signaling molecules. There was a difference between sarcomatoid and epithelioid cells in the activation of two proteins in the so-called Bcl-family. Sarcomatoid cells clearly overexpressed a protein called Bax. Perhaps this is part of the reason why they are more sensitive to selenite.
There is a “master regulator” of apoptosis called p53, and we investigated it rather thoroughly. It turned out that the cells amassed lots of p53 in their nuclei after selenite treatment, but it didn’t do anything! Normally, it would regulate the DNA and determine which genes should be read. But after selenite treatment, p53 became inactive and unable to regulate gene expression.
My greatest surprise was that the apoptosis signaling network was so robust and redundant. It’s really not a well-defined linear cascade of events, but rather an interlaced network of protein interactions which depend on and modulate each other. In this paper, we found that inhibition of some of the major apoptosis-signalling proteins had virtually no effect at all on the events following selenite treatment, even though we could prove that the inhibitors were effective in themselves.
What are the implications for the future?
We hope that selenite will become a useful drug for the treatment of mesothelioma in the future. If so, part of its mechanism of action has now been established.
Check out the full paper, it’s open access!
Nilsonne, G., Olm, E., Szulkin, A., Mundt, F., Stein, A., Kocic, B., Rundlöf, A., Fernandes, A., Björnstedt, M., & Dobra, K. (2009). Phenotype-dependent apoptosis signalling in mesothelioma cells after selenite exposure Journal of Experimental & Clinical Cancer Research, 28 (1) DOI: 10.1186/1756-9966-28-92