Evidence for a role of heat shock factor 1 in inhibition of NF-κB pathway during heat shock response-mediated lung protection

Wirth, Delphine; Bureau, Fabrice; Mélotte, Dorothée; Christians, Elisabeth; Gustin, Pascal

doi:10.1152/ajplung.00184.2003

Cited by 37 publications

(25 citation statements)

References 45 publications

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“…More interestingly, p50 homodimers are translocated into nuclei and activated in Hsp27-overexpressing MCF-7/adr cells that are known to repress NF-B activity. Various models have shown that HSF-1 and NF-B mutually repress (63,64). Thus, the absence of HSF-1 activity led to activation of mutant p53 and NF-B, which in turn can bind in the MDR1 promoter and transcribe P-gp in MCF-7/adr cells.…”

Section: Discussionmentioning

confidence: 99%

Forced Expression of Heat Shock Protein 27 (Hsp27) Reverses P-Glycoprotein (ABCB1)-mediated Drug Efflux and MDR1 Gene Expression in Adriamycin-resistant Human Breast Cancer Cells

Kanagasabai¹,

Krishnamurthy²,

Druhan

et al. 2011

Journal of Biological Chemistry

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Mutant p53 accumulation has been shown to induce the multidrug resistance gene (MDR1) and ATP binding cassette (ABC)-based drug efflux in human breast cancer cells. In the present work, we have found that transcriptional activation of the oxidative stress-responsive heat shock factor 1 (HSF-1) and expression of heat shock proteins, including Hsp27, which is normally known to augment proteasomal p53 degradation, are inhibited in Adriamycin (doxorubicin)-resistant MCF-7 cells (MCF-7/adr). Such an endogenous inhibition of HSF-1 and Hsp27 in turn results in p53 mutation with gain of function in its transcriptional activity and accumulation in MCF-7/adr. Also, lack of HSF-1 enhances nuclear factor B (NF-B) DNA binding activity together with mutant p53 and induces MDR1 gene and P-glycoprotein (P-gp, ABCB1), resulting in a multidrug-resistant phenotype. Ectopic expression of Hsp27, however, significantly depleted both mutant p53 and NF-B (p65), reversed the drug resistance by inhibiting MDR1/P-gp expression in MCF-7/ adr cells, and induced cell death by increased G 2 /M population and apoptosis. We conclude from these results that HSF-1 inhibition and depletion of Hsp27 is a trigger, at least in part, for the accumulation of transcriptionally active mutant p53, which can either directly or NF-B-dependently induce an MDR1/P-gp phenotype in MCF-7 cells. Upon Hsp27 overexpression, this pathway is abrogated, and the acquired multidrug resistance is significantly abolished so that MCF-7/adr cells are sensitized to Dox. Thus, clinical alteration in Hsp27 or NF-B level will be a potential approach to circumvent drug resistance in breast cancer.Development of a multidrug-resistant phenotype is a major obstacle to the successful treatment of breast cancer (1, 2). There are two major pathways by which cancer cells acquire drug resistance, drug efflux and direct suppression of apoptosis. Drug efflux is due to increased plasma membrane accumulation of various ATP-binding cassette (ABC) 2 transporters, including ABCB1, also known as P-glycoprotein (P-gp), which extrude the internalized drugs from the cancer cells (3-5). Various approaches have been reported to overcome the drug efflux, including pharmacological inhibition of ABCs and modulation of endogenous regulators of MDR1 (6). Drug resistance is also acquired via direct suppression of apoptotic pathways due to accumulation of mutant p53 (mutp53) with "gain of function" (7, 8) and increased expression of antiapoptotic proteins, such as BCl-2 (4). In addition to abrogating the proapoptotic function of wild type p53 (wtp53), these p53 missense mutations have been shown to have unusual gain of function properties both in vitro and in vivo (9 -11). Recent studies have established a link between these two pathways of drug resistance (12).Mutant p53 has been found to be the prominent common mediator of both pathways (11). Wild type p53 is generally known to repress the expression of the MDR1 gene, which codes for the ABC protein P-gp through interaction with basal transcription facto...

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Section: Discussionmentioning

confidence: 99%

Forced Expression of Heat Shock Protein 27 (Hsp27) Reverses P-Glycoprotein (ABCB1)-mediated Drug Efflux and MDR1 Gene Expression in Adriamycin-resistant Human Breast Cancer Cells

Kanagasabai¹,

Krishnamurthy²,

Druhan

et al. 2011

Journal of Biological Chemistry

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“…6,61 Under these conditions, heat shock proteins were implicated in NF-B inhibition. 62 In contrast, we used 40°C heat exposure for 60 minutes, thereby mimicking short-term fever spikes that are commonly observed in patients with systemic infections. Previously, we found no evidence that under these conditions neutrophils up-regulated expression of heat shock proteins, even when assayed up to 4 hours (eg, HSP70 and HSP90).…”

Section: Discussionmentioning

confidence: 99%

Short-Term Heat Exposure Inhibits Inflammation by Abrogating Recruitment of and Nuclear Factor-κB Activation in Neutrophils Exposed to Chemotactic Cytokines

Choi

Salanova

Rolle

et al. 2008

The American Journal of Pathology

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Cytokines, such as granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin (IL)-8 attract neutrophils into inflammatory sites. During emigration from the blood neutrophils interact with extracellular matrix proteins such as fibronectin. Fibronectin provides ␤2-integrin co-stimulation, allowing GM-CSF and IL-8 to activate nuclear factor (NF)-B, an effect that does not occur in suspension. We tested the hypothesis that exposure of mice to fever-like temperatures abrogates neutrophil recruitment and NF-B activation in a mouse model of skin inflammation. Mice that were exposed to 40°C for 1 hour showed strongly reduced GM-CSF-and IL-8-induced neutrophilic skin inflammation. In vitro heat exposure did not interfere with neutrophil adhesion or spreading on fibronectin but strongly inhibited migration toward both cytokines. Using specific inhibitors, we found that PI3-K/Akt was pivotal for neutrophil migration and that heat down-regulated this pathway. Furthermore, neutrophils on fibronectin showed abrogated NF-B activation in response to GM-CSF and IL-8 after heat. In vivo heat exposure of mice followed by ex vivo stimulation of isolated bone marrow neutrophils confirmed these results. Finally, less NF-B activation was seen in the inflammatory lesions of mice exposed to fever-like temperatures as demonstrated by in situ hybridization for IB␣ mRNA. These new findings suggest that heat may have anti-inflammatory effects in neutrophil-dependent inflammation. (Am J Pathol

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“…In addition, Hsf1 is required for normal development of the placenta, and female Hsf1 −/− mice are infertile (Xiao et al 1999;Christians et al 2000). Hsf1 −/− mice are more susceptible to lipopolysaccharide-induced mortality, cadmium-induced pulmonary damage, and hydrochloric acid-or ethanol-induced gastric lesions (Xiao et al 1999;Wirth et al 2004;Tanaka et al 2007). In the auditory system, Hsf1 −/− mice demonstrate increased susceptibility to noise trauma (Sugahara et al 2003;Fairfield et al 2005).…”

Section: Figmentioning

confidence: 99%

Hsp70 Inhibits Aminoglycoside-Induced Hair Cell Death and is Necessary for the Protective Effect of Heat Shock

Taleb

Brandon

Lee

et al. 2008

JARO

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Sensory hair cells of the inner ear are sensitive to death from aging, noise trauma, and ototoxic drugs. Ototoxic drugs include the aminoglycoside antibiotics and the antineoplastic agent cisplatin. Exposure to aminoglycosides results in hair cell death that is mediated by specific apoptotic proteins, including cJun N-terminal kinase (JNK) and caspases. Induction of heat shock proteins (Hsps) is a highly conserved stress response that can inhibit JNK-and caspasedependent apoptosis in a variety of systems. We have previously shown that heat shock results in a robust upregulation of Hsps in the hair cells of the adult mouse utricle in vitro. In addition, heat shock results in significant inhibition of both cisplatin-and aminoglycoside-induced hair cell death. In our system, Hsp70 is the most strongly induced Hsp, which is upregulated over 250-fold at the level of mRNA 2 h after heat shock. Therefore, we have begun to examine the role of Hsp70 in mediating the protective effect of heat shock. To determine whether Hsp70 is necessary for the protective effect of heat shock against aminoglycoside-induced hair cell death, we utilized utricles from Hsp70.1/3 −/− mice. While heat shock inhibited gentamicin-induced hair cell death in wild-type utricles, utricles from Hsp70.1/3 −/− mice were not protected. In addition, we have examined the role of the major heat shock transcription factor, Hsf1, in mediating the protective effect of heat shock. Utricles from Hsf1 −/− mice and wild-type littermates were exposed to heat shock followed by gentamicin. The protective effect of heat shock on aminoglycoside-induced hair cell death was only observed in wildtype mice and not in Hsf1 −/− mice. To determine whether Hsp70 is sufficient to protect hair cells, we have utilized transgenic mice that constitutively overexpress Hsp70. Utricles from Hsp70-overexpressing mice and wild-type littermates were cultured in the presence of varying neomycin concentrations for 24 h. The Hsp70-overexpressing utricles were significantly protected against neomycin-induced hair cell death at moderate to high doses of neomycin. This protective effect was achieved without a heat shock. Taken together, these data indicate that Hsp70 and Hsf1 are each necessary for the protective effect of heat shock against aminoglycoside-induced death. Furthermore, overexpression of Hsp70 alone significantly inhibits aminoglycoside-induced hair cell death.

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Evidence for a role of heat shock factor 1 in inhibition of NF-κB pathway during heat shock response-mediated lung protection

Cited by 37 publications

References 45 publications

Forced Expression of Heat Shock Protein 27 (Hsp27) Reverses P-Glycoprotein (ABCB1)-mediated Drug Efflux and MDR1 Gene Expression in Adriamycin-resistant Human Breast Cancer Cells

Forced Expression of Heat Shock Protein 27 (Hsp27) Reverses P-Glycoprotein (ABCB1)-mediated Drug Efflux and MDR1 Gene Expression in Adriamycin-resistant Human Breast Cancer Cells

Short-Term Heat Exposure Inhibits Inflammation by Abrogating Recruitment of and Nuclear Factor-κB Activation in Neutrophils Exposed to Chemotactic Cytokines

Hsp70 Inhibits Aminoglycoside-Induced Hair Cell Death and is Necessary for the Protective Effect of Heat Shock

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