Regulation of mRNA translation by hypoxia in vivo: contribution to hypoxia tolerance and potential for therapy
10 / 2007 - onbekend
Tumor-cellen kunnen zich aanpassen aan zuurstofarme omstandigheden en, door aktivatie van mechanismen die eiwit-produktie remmen, dit zuurstof tekort overleven. Dit onderzoek gaat bepalen of aangrijpen op deze mechanismen een nieuwe therapie kan zijn voor het doden van deze cellen.
Hypoxia is a common feature of solid tumours that contributes to poor outcome by reducing sensitivity to treatment and promoting metastases. Extensive research is currently being performed to characterise the biological mechanisms responsible for these effects. This research mainly focuses on HIF-1 mediated transcriptional responses. However, recent evidence implicates regulation of mRNA translation as another contributor to hypoxia tolerance1. In our group, it was shown that hypoxia regulates mRNA translation through two distinct pathways; 1)by the endoplasmic reticulum kinase (PERK) and 2)by the mammalian target of rapamycin (mTOR)2. Although several studies implicate an important role for PERK and mTOR in the hypoxic response, investigations have not adequately addressed their role in gene expression and tumour maintenance in vivo or their potential as targets for therapy. Here, I hypothesize that disruption of translational control by hypoxia will sensitize the tumour to both hypoxia and anticancer therapies.To test this hypothesis, I have established a unique model that enables us to create isogenic transgenic cancer cells. Transgenes are inducible with tetracycline and cause either over-expression or repression (through RNAi) of target genes. To closely mimic the clinical situation, tumours establish with a wild type genotype and subsequently transgenes are turned on to interfere with hypoxic response pathways. Unlike our model, the models described so far use normal constitutive transgenic or knockout cells and are unable to dissect the roles of these pathways in development and establishment of the tumour from their effectiveness as targets for treatment. Moreover, our approach allows comparison of the contribution and effectiveness of various hypoxic targets in the same genetic background, overcoming a general disadvantage of tumour models used until now. This will allow proper evaluation of the importance of pathways involving HIF-1, PERK and mTOR for tumour growth, gene expression and their potential as molecular targets.