Heat Shock Proteins: Cell Protection through Protein Triage

Lanneau, David; Wettstein, Guillaume; Bonniaud, Philippe; Garrido, Carmen

doi:10.1100/tsw.2010.152

Cited by 162 publications

(121 citation statements)

References 56 publications

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“…Importantly, a conserved feature of HSP90 inhibition is the induction of the cellular heat shock response, most notably characterized by upregulation of the stress-inducible molecular chaperone HSP70. HSP70 plays a critical role in the triage of damaged proteins following proteotoxic stress, in part facilitating a shift in chaperone activity from protein folding to degradation if the protein cannot be effectively renatured (11). In the clinical setting, HSP70 upregulation is commonly used as a pharmacodynamic biomarker for HSP90 inhibition (12,13).…”

Section: Introductionmentioning

confidence: 99%

mTOR Inhibition Potentiates HSP90 Inhibitor Activity via Cessation of HSP Synthesis

Acquaviva

Sang

et al. 2014

Molecular Cancer Research

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Because of their pleiotropic effects on critical oncoproteins, inhibitors of HSP90 represent a promising new class of therapeutic agents for the treatment of human cancer. However, pharmacologic inactivation of HSP90 subsequently triggers a heat shock response that may mitigate the full therapeutic benefit of these compounds. To overcome this limitation, a clinically feasible method was sought to block HSP synthesis induced by the potent HSP90 inhibitor ganetespib. An immunoassay screen of 322 late-stage or clinically approved drugs was performed to uncover compounds that could block upregulation of the stress-inducible HSP70 that results as a consequence of HSP90 blockade. Interestingly, inhibitors of the phosphoinositide 3-kinase (PI3K)/mTOR class counteracted ganetespibinduced HSP70 upregulation at both the gene and protein level by suppressing nuclear translocation of heat shock factor 1 (HSF1), the dominant transcription factor controlling cellular stress responses. This effect was conserved across multiple tumor types and was found to be regulated, in part, by mTOR-dependent translational activity. Pretreatment with cycloheximide, PI3K/mTOR inhibitor, or an inhibitor of eIF4E (a translation initiation factor and downstream effector of mTOR) all reduced ganetespib-mediated nuclear HSF1 accumulation, indicating that mTOR blockade confers a negative regulatory effect on HSF1 activity. Moreover, combined therapy regimens with mTOR or dual PI3K/mTOR inhibitors potentiated the antitumor efficacy of ganetespib in multiple in vivo models.

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Section: Introductionmentioning

confidence: 99%

mTOR Inhibition Potentiates HSP90 Inhibitor Activity via Cessation of HSP Synthesis

Acquaviva

Sang

et al. 2014

Molecular Cancer Research

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“…Heat shock proteins (HSP) are chaperones that catalyze the proper folding of nascent proteins and the refolding of denatured proteins (Lanneau et al 2010). Although they were originally described as proteins induced by Bheat shock,Ĥ SP respond to a variety of brain injuries, including hypoxic ischemia (Dienel et al 1986;Ferriero et al 1990;Dwyer and Nishimura 1992;Kinouchi et al 1993a, b;Currie et al 2000;Sharp et al 2000).…”

mentioning

confidence: 99%

Hypothermia decreased the expression of heat shock proteins in neonatal rat model of hypoxic ischemic encephalopathy

Lee

Jung

Lee

et al. 2017

Cell Stress and Chaperones

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Hypothermia (HT) is a well-established neuroprotective strategy against neonatal hypoxic ischemic encephalopathy (HIE). The overexpression of heat shock proteins (HSP) has been shown to provide neuroprotection in animal models of stroke. We aimed to investigate the effect of HT on HSP70 and HSP27 expression in a neonatal rat model of HIE. Seven-day-old rat pups were exposed to hypoxia for 90 min to establish the Rice-Vannucci model and were assigned to the following four groups: hypoxic injury (HI)-normothermia (NT, 36°C), HI-HT (30°C), sham-NT, and sham-HT. After temperature intervention for 24 h, the mRNA and protein expression of HSP70 and HSP27 were measured. The association between HSP expression and brain injury severity was also evaluated. The brain infarct size was significantly smaller in the HI-HT group than in the HI-NT group. The mRNA and protein expression of both HSPs were significantly greater in the two HI groups, compared to those in the two sham groups. Moreover, among the rat pups subjected to HI, HT significantly reduced the mRNA and protein expression of both HSPs. The mRNA expression level of the HSPs was proportional to the brain injury severity. Post-ischemic HT, i.e., a cold shock attenuated the expression of HSP70 and HSP27 in a neonatal rat model of HIE. Our study suggests that neither HSP70 nor HSP27 expression is involved in the neuroprotective mechanism through which prolonged HT protects against neonatal HIE.

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“…102,103 If they can't refold correctly the abnormal protein, HSPs can facilitate their proteasomal degradation. 104 In case of a cell death stimulus, HSPs are overexpressed and have strong anti-apoptotic properties by associating to different key proteins of the apoptosis transduction signaling pathway. 105 HSPs can also be extracellular (membrane-bound or free after secretion).…”

Section: Heat Shock Proteins and Exosomesmentioning

confidence: 99%

Exosomes in cancer theranostic: Diamonds in the rough

Cordonnier

Chanteloup

Isambert

et al. 2017

Cell Adhesion & Migration

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During the last 10 years, exosomes, which are small vesicles of 50-200 nm diameter of endosomal origin, have aroused a great interest in the scientific and clinical community for their roles in intercellular communication in almost all physiological and pathological processes. Most cells can potentially release these nanovesicles that share with the parent cell a similar lipid bilayer with transmembrane proteins and a panel of enclosed soluble proteins such as heat shock proteins and genetic material, thus acting as potential nanoshuttles of biomarkers. Exosomes surface proteins allow their targeting and capture by recipient cells, while the exosomes' content can modify the physiological state of recipient cells. Tumor derived exosomes by interacting with other cells of the tumor microenvironment modulate tumor progression, angiogenic switch, metastasis, and immune escape. Targeting tumor-derived exosomes might be an interesting approach in cancer therapy. Furthermore, because a key issue to improve cancer patients' outcome relies on earlier cancer diagnosis (metastases, as opposed to the primary tumor, are responsible for most cancer deaths) exosomes have been put forward as promising biomarker candidates for cancer diagnosis and prognosis. This review summarizes the roles of exosomes in cancer and clinical interest, focusing on the importance of exosomal heat shock proteins (HSP). The challenges of clinical translation of HSPexosomes as therapeutic targets and biomarkers for early cancer detection are also discussed.

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Heat Shock Proteins: Cell Protection through Protein Triage

Cited by 162 publications

References 56 publications

mTOR Inhibition Potentiates HSP90 Inhibitor Activity via Cessation of HSP Synthesis

mTOR Inhibition Potentiates HSP90 Inhibitor Activity via Cessation of HSP Synthesis

Hypothermia decreased the expression of heat shock proteins in neonatal rat model of hypoxic ischemic encephalopathy

Exosomes in cancer theranostic: Diamonds in the rough

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