Research Interests

Unfolded Protein Response (UPR)

The unfolded protein response (UPR) is a quality control process that ensures the correct folding, processing, export or degradation of protein emerging from the endoplasmic reticulum (ER).  Activation of the UPR results in a bias of translation towards the synthesis of chaperone proteins involved in protein folding, an increase in disposal of misfolded proteins via the ubiquitin proteasome pathway, and the delivery of a cell survival signal. If the build-up of misfolded protein is irreversible, the cell undergoes apoptosis.

As myeloma cells produce large amounts of immunoglobulin within the ER, they rely heavily on the UPR pathway and other protein turnover pathways for cell survival.  Our work aims to characterise the important intracellular protein turnover pathways in myeloma, with the aim of identifying novel therapeutic compounds targeted against them.  We use myeloma as a model to test our hypothesis but it is clear that a number of secretory solid tumours also rely heavily on protein turnover for cell survival and metastatic potential and therefore the results will be applicable to other tumours.

Davenport EL, Aronson LI, Davies FE. Starving to succeed.  Autophagy. 2009:14;5(7). Click to enlarge

Our work has shown that inhibiting the function of the UPR results in myeloma cell death.  In addition we have demonstrated that one component of the UPR, the XBP1/IRE1 pathway, plays a central role in myeloma cell biology and levels of the active transcription factor XBP1s are prognostically significant.  Our ongoing work is characterising the UPR pathway more fully in myeloma with a view to targeting it therapeutically.

We have also shown that it is possible to manipulate the UPR by inducing stress.  A cell placed under such stress has two possible physiological responses.  Initially it will resist death whilst attempts at correct protein folding are carried out, however, if this fails then an apoptotic signal is delivered.  One approach to generate ER stress is to target heat shock proteins (HSP).  This family of proteins act as molecular chaperones to ensure correct protein folding and are key mediators of the UPR within the ER.  They also have a broader anti-apoptotic role mediating both the intrinsic mitochondrial dependent and extrinsic death receptor dependent apoptotic pathways, and have been shown to mediate drug resistance.  The central and diverse role of the HSPs suggests that manipulating their activity to induce ER stress and the UPR offers a potential anti-myeloma approach.  To date our data shows that inhibiting HSP90 results in a decrease in client proteins sensitising cells to apoptosis, as well as preventing correct protein folding leading to increased ER stress and myeloma cell death.  Our on going work is exploring the role of other heat shock protein family members in this process.

Finally we have also been exploring the close link between activation of the UPR and a further protein degradation pathway, autophagy.  Under conditions of stress such as the presence of aggregated proteins nutrient deprivation, or hypoxia, autophagy is upregulated.  This results in the activation of the beclin/PI3 kinase class III complex and the ubiquitin-like conjugation enzyme systems that enable double membrane vesicles to enclose unwanted aggregate proteins in an autophagosome.  As well as removing the immediate stress, this process also results in the recycling of amino acids as the autophagosome fuses with lysosomes, delivering its contents for degradation by lysosomal enzymes. Our work suggests that the activation of autophagy in myeloma assists in tumour cell survival, and therefore targeting the pathway may result in the development of a novel approach to myeloma therapy.