title: Autophagy, protein aggregation and hyperthermia: a mini-review.
abstract: OBJECTIVE
  We aim to explore the role of macroautophagy in cellular responses to hyperthermia. Protein damage incurred during hyperthermia can either lead to cell death or may be repaired by polypeptide quality control pathways including: (1) the deterrence of protein unfolding by molecular chaperones and (2) proteolysis of the denatured proteins within the proteasome. A third pathway of protein quality control is triggered by formation of protein aggregates in the heat shocked cell. This is the macroautophagy pathway in which protein aggregates are transported to specialised organelles called autolysosomes capable of degrading the aggregates. The consequences for cell viability of triggering this pathway are complex and may involve cell death, although under many circumstances, including exposure of cells to hyperthermia, autophagy leads to enhanced cell survival. We have discussed mechanisms by which cells detect protein aggregates and recruit them into the macroautophagy pathway as well as the potential role of inhibiting this process in hyperthermia.
  
  
  CONCLUSIONS
  Directed macroautophagy, with its key role in protein quality control, seems an attractive target for a therapy such as hyperthermia that functions principally through denaturing the proteome. However, much work is needed to decode the mechanisms of thermal stress-mediated macroautophagy and their role in survival/death of cancer cells before recommendations can be made on targeting this pathway in combination with hyperthermia.
authors.affiliation: Molecular and Cellular Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School , 99 Brookline Avenue, Boston, MA 02215 , USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.forename: Stuart K
authors.initials: SK
authors.lastname: Calderwood
mesh_terms: D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D002470:Cell Survival / Q000502:physiology; D005334:Fever / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D006801:Humans; D006979:Hyperthermia, Induced; D008247:Lysosomes / Q000502:physiology; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism; D008565:Membrane Proteins / Q000502:physiology; D018832:Molecular Chaperones / Q000502:physiology; D009369:Neoplasms / Q000628:therapy; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011489:Protein Denaturation; D058767:Protein Unfolding; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D058570:TOR Serine-Threonine Kinases; D048728:MAP Kinase Kinase Kinase 1; D046988:Proteasome Endopeptidase Complex