Download Research group Tumour Hypoxia

Research group Tumour Hypoxia
In the first line of research in our lab we attempt to understand the molecular
pathways that allow tumor cells to survive for long periods of hypoxia. These
?hypoxia-tolerance? mechanisms may become attractive targets for overcoming the
problem of hypoxia in cancer.
The rate of protein synthesis decreases to ~30% of control levels within 1 hour after
the onset of hypoxia. Since protein synthesis is one of the highest energy consuming
pathways in hypoxic cells, it is postulated that this decrease serves to conserve
energy and thereby promote survival. Furthermore, regulation of protein synthesis
affects the expression of certain genes that may also promote hypoxia tolerance.
Thus, it is expected that if tumor cells are unable to down-regulate protein synthesis
during hypoxia, they should be less tolerant of hypoxia.
Our preliminary work has resulted in the identification of two molecular pathways
that are important for the regulation of translation during hypoxia, i.e. the unfolded
protein response and mTOR. The unfolded protein response consists of 3 parralell
signalling pathways, initiated by activation of PERK, ATF6 or IRE-1 respectively.
Although the PERK-branch is directly involved in regulation of mRNA synthesis, more
evidence is gathered that the other two play important roles in hypoxia-tolerance
too. To address this we will interfere on different levels within these cascades.
Furthermore, we have shown that a process called autophagy (self-eating) is highly
activated during hypoxia. It is unclear whether this mechanism is activated to
remove damaged or obsolete organelles, or is involved in energy-production during
this period where it lacks oxygen. Cells unable to complete the full autophagic
process are very sensitive towards oxygen deprivation and targeting this pathway
may therefore be an opportunity to enhance tumor therapy. To further elucidate the
role of autophagy during hypoxia and to find the best suitable target, several
proteins in the signalling pathway will be investigated