New approach in battle against colorectal cancer
FAU researchers discover mechanism which can inhibit cell growth
Growth of colorectal cancer cells can be greatly reduced. A team of researchers led by Dr. Dominic Bernkopf from the Chair of Experimental Medicine II (Molecular Oncology) at FAU has developed a peptide which is capable of penetrating colorectal cancer cells and significantly decelerating their growth rate. The scientists have published their recent research findings, funded by the Interdisciplinary Centre for Clinical Research (IZKF) at FAU, in the journal Nature Communications.
Colorectal cancer is a malignant tumour in the large intestine or rectum, and is one of the most common forms of cancer worldwide. The disease affects 483,000 people in Germany alone. ‘In over 90 percent of all cases of colorectal cancer the Wnt signalling pathway shows increased activity, thus contributing to tumour growth,’ explains Dr. Bernkopf. The Wnt signalling pathway is a type of biochemical network in cells which is usually strictly regulated in healthy cells. In tumour cells, however, the Wnt signalling pathway acts uncontrollably, leading to increased cell division and encouraging the growth of the tumour. ‘When Wnt signaling pathway activity is increased, more conductin is produced,’ continues Bernkopf, an expert in molecular medicine. Conduction, also known as axin2, is a negative regulator of the Wnt signalling pathway and ensures that the Wnt signalling pathway is not activated excessively in healthy cells. ‘In tumour cells, however, even large quantities of conductin are not sufficient to prevent the growth of tumours. This is where our research comes in.’
New mechanism discovered
The research group at the Chair of Experimental Medicine II (Molecular Oncology) led by Prof. Dr. Jürgen Behrens has now discovered a new mechanism which can lead to increased conductin activity. ‘We succeeded in developing a short peptide which penetrates the cancer cells, attaches to the conductin and thereby initiates the polymerisation of conductin to a high molecular weight complex,’ says Dr. Dominic Bernkopf. The new complexes formed from conductin proteins are considerably more active than the conductin scattered throughout the cells. They specifically suppress the signalling pathway which causes cell growth in nearly all instances of colorectal cancer. ‘The crucial fact is that our peptide significantly inhibited the growth of colorectal cancer cells during our research,’ summarises Dr. Bernkopf. ‘Our peptide has the potential to act as a new, targeted therapy for colorectal cancer. However, its efficacy first has to be proved in vitro, then confirmed in clinical studies.’
Research on axin and conductin
The researchers are focusing on the scaffold proteins axin and conductin. Whilst both fulfil the same function – they are key factors for negative regulation of the Wnt signalling pathway – they have significant differences. ‘Our data shows that axin, which forms polymers from the outset, is considerably more active than conducin,’ explains Dr. Bernkopf. ‘We wanted to find out why that is the case and which domains are responsible for the differences in behaviour between the two proteins.’ A protein can consist of one or several domains, a domain is usually a coherent segment of the amino acid sequence. ‘We conducted experiments in which we swapped individual domains between axin and conductin,’ says Dr. Bernkopf. Surprisingly, we noted that only the RGS domains determined the distribution pattern of axin and conductin. Whilst the axin-RGS domain allows polymerisation, the conductin-RGS domain impedes this reaction sequence.’ Based on these findings, the researchers developed a short peptide which circumvented the weakness in conductin and made polymerisation possible.
Dr. Dominic Bernkopf
Phone: +49 9131 8529115