Intracellular Targeting of Heat Shock Proteins in Differentiated Human Neuronal Cells Following Proteotoxic Stress

Heat shock proteins (HSPs) are found at elevated concentrations in tumour cells, and this increase reflects the proteotoxic stress experienced by the cells due to expanding levels of the mutated oncoproteins that drive tumorigenesis. The protection of oncogenic proteins by HSPs offers a window of vulnerability in tumour metabolism that has been exploited using Hsp90-targeting drugs. Such compounds have been shown to cause inhibition and degradation of a wide range of proteins essential for oncogenesis. Recently, Hsp90 has also been shown to be secreted by tumour cells and to interact in autocrine or paracrine manners with the surfaces of adjacent cells, leading to increased growth and metastasis. Future studies will address a number of key questions associated with these findings, including the relative importance of intracellular versus extracellular HSPs in tumorigenesis, as well as overcoming potential problems with normal tissue toxicity associated with Hsp90 drugs. Targeting individual members of HSP families and inactivating extracellular HSPs may be desirable future approaches that offer increased selectivity in targeting HSPs in cancer. This article is part of the theme issue ‘Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective’.

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Comparison of labeled heat shock proteins in neuronal and non-neuronal cells of Aplysia californica

Journal of Neuroscience ◽

10.1523/jneurosci.05-05-01239.1985 ◽

1985 ◽

Vol 5 (5) ◽

pp. 1239-1245 ◽

Cited By ~ 21

Author(s):

SG Greenberg ◽

RJ Lasek

Keyword(s):

Heat Shock ◽

Heat Shock Proteins ◽

Neuronal Cells ◽

Aplysia Californica ◽

Shock Proteins

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Heat Shock Proteins hsp90 and hsp70 Protect Neuronal Cells from Thermal Stress but Not from Programmed Cell Death

Journal of Neurochemistry ◽

10.1046/j.1471-4159.1994.63051787.x ◽

2002 ◽

Vol 63 (5) ◽

pp. 1787-1795 ◽

Cited By ~ 77

Author(s):

Carolina Mailhos ◽

M. Keith Howard ◽

David S. Latchman

Keyword(s):

Cell Death ◽

Thermal Stress ◽

Heat Shock ◽

Programmed Cell Death ◽

Heat Shock Proteins ◽

Neuronal Cells ◽

Shock Proteins

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The heat-shock, or HSF1-mediated proteotoxic stress, response in cancer: from proteomic stability to oncogenesis

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2016.0525 ◽

2017 ◽

Vol 373 (1738) ◽

pp. 20160525 ◽

Cited By ~ 24

Author(s):

Chengkai Dai

Keyword(s):

Stress Response ◽

Heat Shock ◽

Heat Shock Proteins ◽

Protein Misfolding ◽

Heat Shock Factor 1 ◽

Growth And Survival ◽

Proteotoxic Stress ◽

Shock Proteins ◽

Misfolding Diseases

The heat-shock, or HSF1-mediated proteotoxic stress, response (HSR/HPSR) is characterized by induction of heat-shock proteins (HSPs). As molecular chaperones, HSPs facilitate the folding, assembly, transportation and degradation of other proteins. In mammals, heat shock factor 1 (HSF1) is the master regulator of this ancient transcriptional programme. Upon proteotoxic insults, the HSR/HPSR is essential to proteome homeostasis, or proteostasis, thereby resisting stress and antagonizing protein misfolding diseases and ageing. Contrasting with these benefits, an unexpected pro-oncogenic role of the HSR/HPSR is unfolding. Whereas HSF1 remains latent in primary cells without stress, it becomes constitutively activated within malignant cells, rendering them addicted to HSF1 for their growth and survival. Highlighting the HSR/HPSR as an integral component of the oncogenic network, several key pathways governing HSF1 activation by environmental stressors are causally implicated in malignancy. Importantly, HSF1 impacts the cancer proteome systemically. By suppressing tumour-suppressive amyloidogenesis, HSF1 preserves cancer proteostasis to support the malignant state, both providing insight into how HSF1 enables tumorigenesis and suggesting disruption of cancer proteostasis as a therapeutic strategy. This review provides an overview of the role of HSF1 in oncogenesis, mechanisms underlying its constitutive activation within cancer cells and its pro-oncogenic action, as well as potential HSF1-targeting strategies. This article is part of the theme issue ‘Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective’.

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