The cellular protein, a member of the p53 family, makes the cell more receptive to chemotherapy, opening up new possibilities for researchers to overcome resistance to medicinal drug treatment.
In addition, the discovery of this protein facilitates further research into additional molecules that induce cell death, in which scientists hope to find new insights and approaches that make it possible to treat cancer pharmaceutically in a more specific manner.
The investigators identified molecular mechanisms by which the protein, TAp63alpha, triggers programmed cell death (apoptosis). To preserve an organism, old or damaged cells are "sentenced to death". Cellular control molecules such as p53 induce programmed cell death, ensuring the cell is no longer able to multiply. Failure of this mechanism can lead to unrestricted cell division and to cancer.
Chemotherapy makes use of a cell's suicide mechanism by signalling from outside that it is time to die. In cancer cells, the control molecules involved in the death program are often transformed in such a way that they are no longer able to fulfil their function properly. If cytotoxins have no "accomplice" in the cell interior, chemotherapy is usually destined to fail resulting in chemoresistance.
Multidrug resistance is often caused by an increase in the cell's production of proteins that transport drugs out of the cell, preventing the drugs from combating cancer. Resistance to treatment with anticancer drugs can also result from a variety of factors including individual variations in patients and somatic cell genetic differences in tumours, even those from the same tissue of origin.
In her research, Dr Martina Müller-Schilling, consultant at the University Medical Hospital in Heidelberg, found elevated levels of the control molecule TAp63alpha in cancer cells, which had been treated with various cytotoxins.
In collaboration with Professor Peter Krammer of the German Cancer Research Centre and scientists from Israel, Italy and the United Kingdom, Müller-Schilling found out that TAp63alpha is able to reinforce the production of various "death receptors" such as CD95, TNF-R and TRAIL-R both in liver and bone cancer cells.
These are cell surface sensors whose job it is to mediate death signals from the cell surroundings into the cell interior. Moreover, TAp63alpha activates cellular proteins, e.g. members of the Bcl-2 family, which also start the self-destruction program via the cell's power plants, or mitochondria. In this way, the cell is made receptive to chemotherapy.
Müller-Schilling also performed the experiment in reverse, in which cells whose TAp63alpha gene was switched off developed a resistance to the administered drugs.
Understanding the mechanisms by which tumours become resistant to a particular agent is key to identifying new drugs or combination regimens. While the problem of resistance will always be an ongoing problem for the pharmaceutical industry, new strategies and points of attack will ensure the fight against resistance will be an equal one.
The latest study, by scientists from the Heidelberg University Medical Hospital and the German Cancer Research Centre (Deutsches Krebsforschungszentrum, DKFZ) is published in the latest issue of EMBO Journal.