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Hyperthermia induces Autophagy

Hyperthermia has been shown to induce macroautophagy under range of conditions

We will concentrate here on macroautophagy and its potential role in hyperthermia treatment of cancer. Macroautophagy was originally thought to be a pathway of programmed cell death in complex organisms and molecular determinants of this process could be observed in dying cells. However, recent studies suggest that under many conditions, this process may be beneficial to stressed cells and promote survival . Hyperthermia has been shown to induce macroautophagy under range of conditions and in most cases, triggering of this pathway was associated with increased cell survival and decreased programmed cell death.

http://www.ncbi.nlm.nih.gov/pubmed/21756038

2011;27(5):409-14.

Autophagy, protein aggregation and hyperthermia: a mini-review.

Zhang Y¹, Calderwood SK.

PURPOSE:

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.

http://www.ncbi.nlm.nih.gov/pubmed/25974074

Int J Hyperthermia. 2015;31(5):476-88.

A study of thermal dose-induced autophagy, apoptosis and necroptosis in colon cancer cells.

Mouratidis PX1, Rivens I, Ter Haar G.

Abstract

PURPOSE:

The pleiotropic effects of heat on cancer cells have been well documented. The biological effects seen depend on the temperature applied, and the heating duration. In this study we investigate the cytotoxic effects of heat on colon cancer cells and determine how different cell death processes such as autophagy, apoptosis and necroptosis play a role in cell response.

MATERIALS AND METHODS:

The thermal dose concept was used to provide a parameter that will allow comparison of different thermal treatments. Two human colon cancer cell lines, HCT116 and HT29, were subjected to ablative temperatures using a polymerase chain reaction thermal cycler. Temperature was recorded using thermocouples. Cell viability was assessed using the MTT assay. Induction of apoptosis was estimated using an enzyme-linked immunosorbent assay that detects cleaved cytoplasmic nucleosomes. Protein regulation was determined using immunoblotting. The percentage of cells undergoing apoptosis and autophagy was determined with annexin V/propidium iodide staining and a cationic amphiphilic tracer using fluorescence-activated cell sorting analysis.

RESULTS:

Exposure of colon cancer cells to ablative thermal doses results in decreased cell viability. The cytotoxic effect of heat is associated with induction of apoptosis and autophagy, the amount depending on both the thermal dose applied and on the time elapsed after treatment. Autophagy induction is mainly seen in live cells. RIPK3 protein levels are increased after exposure of cells to heat. A necroptosis inhibitor does not affect cell viability.

CONCLUSIONS:

Autophagy, apoptosis and necroptosis are associated with the response of these cancer cell lines to supra-normal temperatures.

http://www.ncbi.nlm.nih.gov/pubmed/23590364

Int J Hyperthermia. 2013 May;29(3):239-47. doi: 10.3109/02656736.2013.777853.

Attenuating heat-induced cellular autophagy, apoptosis and damage in
H9c2 cardiomyocytes by pre-inducing HSP70 with heat shock preconditioning.

Hsu SF1, Chao CM, Huang WT, Lin MT, Cheng BC.

Abstract

PURPOSE:

We sought to assess whether heat-induced autophagy, apoptosis and cell damage in H9c2 cells can be affected by pre-inducing HSP70 (heat shock protein 70).

MATERIALS AND METHODS:

Cell viability was determined using 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide staining and a lactate dehydrogenase assay. Apoptosis was evidenced using both flow cytometry and counting caspase-3 positive cells, whereas autophagy was evidenced by the increased LC3-II expression and lysosomal activity.

RESULTS:

The viability of H9c2 cells was temperature-dependently (40-44 °C) and time-dependently (90-180 min) significantly (p < 0.05) reduced by severe heat, which caused cell damage, apoptosis and autophagy. Heat-induced cell injury could be attenuated by pretreatment with 3-methylademine (an autophagy inhibitor) or Z-DEVD-FMK (a caspase-3 inhibitor). Neither apoptosis nor autophagy over the levels found in normothermic controls was induced in heat-shock preconditioned controls (no subsequent heat injury). The beneficial effects of mild heat preconditioning (preventing heat-induced cell damage, apoptosis and autophagy) were significantly attenuated by inhibiting HSP70 overexpression with triptolide (Tripterygium wilfordii) pretreatment.

CONCLUSION:

We conclude that pre-inducing HSP70 attenuates heat-stimulated cell autophagy, apoptosis and damage in the heart. However, this requires in vivo confirmation.

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