A stressful life (or death): Combinatorial proteotoxic approaches to cancer-selective therapeutic vulnerability

  • Workman P
  • Davies F
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Abstract

Proteotoxic stress targeted therapy (PSTT): induction of protein misfolding enhances the antitumor effect of the proteasome inhibitor bortezomib. Oncotar-get, 2(3), 209-221. Maintaining protein homeostasis within a cell is vital. Recent studies have suggested that therapeutically manipulating intracellular protein handling pathways in cancer cells perturbs protein homeostasis and results in the delivery of a novel apoptotic signal. A new paper in Oncotarget by Neznanov et al [1] reinforces the potential of proteotoxic stress-targeted therapy and in particular demonstrates the ability of combinatorial approaches to enhance the antitumor effects of the proteasome inhibitor bortezomib by induction of protein misfolding using hyperthermia or the antibiotic puromycin. In particular, the new results illustrate the therapeutic potential of combining non-toxic doses of puromycin with bortezomib in a mouse model of multiple myeloma. There are a number of potential ways of perturbing protein homeostasis: firstly by forcing the apoptotic signal by disturbing protein quality control with the premature degradation of key growth and survival molecules; secondly by inhibiting the degradation of proteins resulting in a build up of unwanted proteins; or finally by interfering with key protein folding pathways resulting in the build-up of misfolded proteins. The end result of each of these processes is programmed cell death. Crucially, malignant cells are more susceptible to killing through the manipulation of proteostasis, resulting in a cancer-selective vulnerability. The build up of proteins that have failed to fold correctly results in the presence of non-functional proteins, a tendency toward protein aggregation and impaired cellular function and is referred to as proteotoxic stress (PS). 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. Two highly conserved systems are in place to combat PS – the unfolded protein response (UPR) and the heat shock response (HSR). Both systems act as quality control processes ensuring the correct folding and 3D conformation for functionally active proteins. The UPR senses unfolded native proteins within the endoplasmic reticulum (ER) and ensures their correct folding, processing, export or degradation. Activation of the UPR results in a bias of protein translation towards the synthesis of chaperone proteins involved in protein folding within the ER, an increase in disposal of misfolded proteins via the ubiquitin proteasome pathway, and the delivery of a survival signal. If the build-up of misfolded protein is irreversible, the cell undergoes apoptosis [2,3]. The HSR is activated by the accumulation of non-native proteins in the cytosol or nucleus. Once activated there is an increase in the synthesis of molecular chaperones that both facilitate protein folding and also suppress protein aggregation. In addition, the heat shock proteins also have a broader anti-apoptotic role mediating both the intrinsic mitochondrial-dependent and extrinsic death receptor-dependent apoptotic pathways [4,5]. The balance, therefore, between the induction of proteotoxic stress and the adaptive UPR and HSR is vital for protein homeostasis and cell survival (Figure 1). A number of studies have demonstrated that cancer cells have intrinsically high levels of PS. This is a result of the accumulation of misfolded proteins caused by cancer cells surviving within an unfavourable hypoxic micro-environment, as well as an increase in protein misfolding

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Workman, P., & Davies, F. E. (2015). A stressful life (or death): Combinatorial proteotoxic approaches to cancer-selective therapeutic vulnerability. Oncotarget, 2(4). https://doi.org/10.18632/oncotarget.266

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