Cancer: Therapeutic Approaches Targeting Stress Pathways

Abstract

Cell stress is a ubiquitous term covering vast forms of perturbations to the homeostatic state of the cell. The response mechanisms to these types of stresses are aimed at protecting the cells and allowing them to recover from the inflicted damage. Before reaching the critical level of stress resulting in stressā€induced cell death, cells utilise these survival strategies to protect themselves from the exposed insult. Tumour cells similarly utilise these survival strategies to continue replication despite their extreme surrounding environment. Survival responses to stress also allow tumour cells to overcome additional challenges presented by treatment regiments such as chemotherapy and radiation, resulting in resistance. These survival pathways, therefore, are being targeted in addition to standard treatment to force the stressed oncogenic cells into their death pathways. Use of these survival pathway inhibitors has markedly increased tumour sensitivity to chemotherapy and radiation, suggesting an alternative approach to cancer therapeutics.

Key Concepts

  • Eukaryotic cells are able to activate multiple stress response pathways when exposed to environmental stress.
  • In cancer cells, these stress response pathways are frequently upregulated to cope with nutrient deprivation, hypoxia, abundance of misfolded proteins, and other stresses common to cancer cells.
  • Many cancer drugs induce cell stress and stimulate one or more cell stress response pathways.
  • Thus, cancer cells use multiple cell stress response pathways to support drug resistance, particularly to cytotoxic agents.
  • Cancer cell sensitivity to cytotoxic drugs may be enhanced by simultaneously blocking cell stress response pathways.

Keywords: heat shock response (HSR); unfolded protein response (UPR); cell death pathways; heat shock proteins (HSPs); GRP78; ataxia telangiectasia mutated (ATM); reactive oxygen species (ROS); superoxide dismutases (SOD)

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Zuehlke, Abbey D, and Neckers, Leonard(Aug 2018) Cancer: Therapeutic Approaches Targeting Stress Pathways. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0027923]