Mitochondrial link with cancer therapy
At the forefront of tools for the treatment of cancer are agents that can induce damage in the cell DNA, as this can automatically trigger cell death. Programmed cell death or apoptosis is an important phenomenon in the cell cycle as it is a natural mechanism for cell termination, cell homeostasis and tissue development. In terms of cancer therapy, cells that respond to treatment have activated apoptotic pathways while tumours resistant to treatment have been shown to display blocked pathways to cell termination. Cells have a large range of genes and regulators involved in apoptosis. As part of a comprehensive study into the pathways involved, project partners of IMPALED investigated the gene identified which encodes the flavoprotein AIF. This was identified as a potential molecular target for the p53 family of proteins that are cellular sensors of DNA damage. It has been discovered that AIF, usually present in the labyrinth of intermembrane spaces found in the cell mitochondrion, is required for cell survival. However, AIF translocates from its usual location into the cell nucleus where it induces DNA fragmentation and cell termination. The researchers found that AIF is positively regulated even when DNA damage is not present. This was considered to be an unusual phenomenon as genotoxic stress causes induction of p53 target genes but has hardly any effect on AIF levels. Moreover, it was shown that the induction of transcription of AIF allows p53 to promote cell death during chemotherapy. Further understanding of the precise mechanism of this relationship may help to optimise the selective nature of cell death for cancer treatment. It is envisaged that further genomic and bioinorganic input from partners will lead to commercial development.
