SP 1

Towards a transcriptome-wide and integrated vision of the translation branch of the unfolded protein response in glioma

The elevated proliferation of cancer cells necessitates a high metabolic rate and elevated protein synthesis. The tumor microenvironment often poses an additional challenge to the tumor cells with limited nutrient availability and hypoxic conditions. In sum, this results in persistent and on-going Endoplasmic Reticulum (ER) stress which triggers the Unfolded Protein Response (UPR), a signaling cascade that aims at reinstating and maintaining cellular homeostasis, controlling cell fate and allowing the cells to persist.
The UPR leads to a transcriptional and translational reprogramming in order to alleviate ER stress. Upon continuous ER stress and when cellular homeostasis cannot be reinstated, the UPR can also trigger apoptosis. Tumor cells make use of the prosurvival response of the UPR while evading apoptosis even in the presence of continuous ER stress. Moreover, it has been demonstrated that the active UPR in tumors conveys chemoresistance. Hence the UPR has emerged as a target for therapeutic intervention with the aim to tilt the balance of the protective effects of the UPR towards the induction of apoptosis in tumors.
In general the UPR utilizes three main branches to sense perturbations in ER homeostasis and to trigger the appropriate cellular responses: inositol-requiring enzyme-1 (IRE1), activating transcription factor 6 (ATF6) and PKR-like endoplasmic reticulum kinase (PERK). While the first two pathways mainly act via transcriptional reprogramming, PERK controls cellular translation via the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2a). Strikingly though, while continuous ER stress (as encountered in tumors) normally results in attenuation of both the IRE1 and ATF6 branches of the UPR, PERK is thought to remain continuously active, suggesting that the PERK branch might be the predominant UPR signal cascade in tumors.
Despite its broad clinical importance, qualitative and quantitative models that describe the UPR in cancer cells are missing so far. We aim for a better understanding of the UPR in glioma in particular in the context of clinically important cell fate decisions such as invasion (‘go versus grow’) or resistance to pharmacological treatment (survival vs. apoptosis). To this end, we employ state of the art methodology to gain novel, deep and systems-wide insights into translation and its regulation during the UPR in glioma.

Keywords: Unfolded Protein Response, Translational Reprogramming, Translational Regulation