Proteasome Inhibitors MG132 and Lactacystin Hyperphosphorylate HSF1 and Induce hsp70 and hsp27 Expression

Kim, Dooha; Kim, Sun‐Hee; Li, Gloria C.

doi:10.1006/bbrc.1998.9840

Cited by 113 publications

(75 citation statements)

References 23 publications

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“…The central role of proteasome inhibition in the activity of LLNle on GBM TICs is further supported by the observation that LLNle induces accumulation of poly-ubiquitinylated proteins that cannot be processed by the inhibited proteasome and by the induction of genes related to the unfolded protein response and endoplasmic reticulum stress (including HSPA1B). Similar results have been previously described in different cell types with proteasome inhibitors (35,36,(52)(53)(54). Furthermore, the close similarity of the chemical structure of LLNle with those of GM132 and N-acetyl-leucyl-leucyl-norleucinal, well-known proteasome inhibitors, should be underlined (55).…”

Section: Discussionsupporting

confidence: 82%

z-Leucinyl-Leucinyl-Norleucinal Induces Apoptosis of Human Glioblastoma Tumor–Initiating Cells by Proteasome Inhibition and Mitotic Arrest Response

Monticone

Biollo

Fabiano

et al. 2009

Molecular Cancer Research

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γ-secretase inhibitors have been proposed as drugs able to kill cancer cells by targeting the NOTCH pathway. Here, we investigated two of such inhibitors, the Benzyloxicarbonyl-Leu-Leu-Nle-CHO (LLNle) and the N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), to assess whether they were effective in killing human glioblastoma tumor-initiating cells (GBM TIC) in vitro. We found that only LLNle was able at the micromolar range to induce the death of GBM TICs by apoptosis. To determine the cellular processes that were activated in GBM TICs by treatment with LLNle, we analyzed the amount of the NOTCH intracellular domain and the gene expression profiles following treatment with LLNle, DAPT, and DMSO (vehicle). We found that LLNIe, beside inhibiting the generation of the NOTCH intracellular domain, also induces proteasome inhibition, proteolytic stress, and mitotic arrest in these cells by repressing genes required for DNA synthesis and mitotic progression and by activating genes acting as mitotic inhibitors. DNA content flow cytometry clearly showed that cells treated with LLNle undergo arrest in the G 2 -M phases of the cell cycle. We also found that DAPT and L-685,458, another selective Notch inhibitor, were unable to kill GBM TICs, whereas lactacystin, a pure proteasome inhibitor, was effective although at a much less extent than LLNle. These data show that LLNle kills GBM TIC cells by inhibiting the proteasome activity. We suggest that LLNle, being able to target two relevant pathways for GBM TIC survival, may have a potential therapeutic value that deserves further investigation in animal models.

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Section: Discussionsupporting

confidence: 82%

z-Leucinyl-Leucinyl-Norleucinal Induces Apoptosis of Human Glioblastoma Tumor–Initiating Cells by Proteasome Inhibition and Mitotic Arrest Response

Monticone

Biollo

Fabiano

et al. 2009

Molecular Cancer Research

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“…25 Moreover, patients with different liver diseases and 'drug-primed' mice that develop Mallory bodies also present an HSR. [26][27][28] Indeed, bortezomib caused an HSR in our mouse model. Figure 6a displays representative images of our findings.…”

Section: Effects Of Bortezomib On Antithrombin D Hernández-espinosa Ementioning

confidence: 65%

Inhibition of proteasome by bortezomib causes intracellular aggregation of hepatic serpins and increases the latent circulating form of antithrombin

Hernández-Espinosa

Miñano

Martı́nez

et al. 2008

Laboratory Investigation

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Conformational diseases include heterogeneous disorders sharing a similar pathological mechanism, leading to intracellular aggregation of proteins with toxic effects. Serpins are commonly involved in these diseases. These are structurally sensitive molecules that modify their folding under even minor genetic or environmental variations. Indeed, under normal conditions, the rate of misfolding of serpins is high and unfolded serpins must be degraded by the proteasome system. Our aim was to study the effects of bortezomib, a proteasome inhibitor, on conformationally sensitive serpins. The effects of bortezomib were analysed in patients with multiple myeloma, HepG2 cells, and Swiss mice, as well as in vitro. Levels, anti-FXa activity, heparin affinity, and conformational features of antithrombin, a relevant anticoagulant serpin, were analysed. Histological, ultrastructural features and immunohistological distribution of antithrombin and a1-antitrypsin (another hepatic serpin) were evaluated. We also studied the intracellular accumulation of conformationally sensitive (fibrinogen) or non-sensitive (prothrombin) hepatic proteins. The inhibition of the proteasome caused intracellular accumulation and aggregation of serpins within the endoplasmic reticulum that was associated with confronting cisternae and Mallory body formation. These effects were accompanied by a heat stress response. Bortezomib also increased the levels of intracellular fibrinogen, but has no significant effect on prothrombin. Finally, bortezomib had only minor effects on the mature circulating antithrombin, with increased amounts of latent antithrombin in plasma. These results suggest that the impairment of proteasomal activities leads to an intracellular accumulation of conformationally sensitive proteins and might facilitate the release of misfolded serpins into circulation where they adopt more stable conformations.

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“…Co-treatment of haemocytes with the proteasome inhibitor MG132 and ESPs largely restored cellular HSP70 levels. MG132 can increase heat shock factor activity in mammalian cells and thus increase intracellular HSP70 expression (Kim et al 1999). However, this inhibitor does not induce de novo synthesis of HSP70 protein in B. glabrata haemocytes as HSP70 expression in MG132-treated cells was similar to that in untreated control haemocytes.…”

Section: Hsp70 Protein Reduction May Be Regulated By Effects Of Esps mentioning

confidence: 88%

“…The inhibitor, U0126, has previously been used at these concentrations to block MEK1/2 activity in B. glabrata and Lymnaea stagnalis haemocytes, subsequently suppressing the phosphorylation (activation) of ERK (Plows et al 2004;Plows et al 2005;Wright et al 2006;Zahoor et al 2008Zahoor et al , 2009). The concentration chosen for MG132 was similar to that used by Kim et al (1999). Immediately after treatment, the medium was removed and haemocyte proteins were extracted by adding hot sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) sample buffer; samples were then sonicated for 30 s and boiled for 1 min.…”

Section: Haemocytes and Haemocyte Treatmentsmentioning

confidence: 99%

“…The protein may have fallen below the detection limit given the larger volume of medium or HSP70 maybe degraded intracellularly by proteasomes or lysosomes. To explore this further, the 26S proteasome-specific inhibitor MG132 was used to inhibit general intracellular protein degradation (Kim et al 1999). Susceptible and resistant snail haemocytes were exposed to Fig.…”

Section: Hsp70 Protein Degradation In Haemocytes Challenged With Espsmentioning

confidence: 99%

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Larval excretory-secretory products from the parasite Schistosoma mansoni modulate HSP70 protein expression in defence cells of its snail host, Biomphalaria glabrata

Zahoor

Davies²,

Kirk³

et al. 2010

Cell Stress and Chaperones

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Synthesis of heat shock proteins (HSPs) following cellular stress is a response shared by many organisms. Amongst the HSP family, the ∼70 kDa HSPs are the most evolutionarily conserved with intracellular chaperone and extracellular immunoregulatory functions. This study focused on the effects of larval excretory-secretory products (ESPs) from the parasite Schistosoma mansoni on HSP70 protein expression levels in haemocytes (defence cells) from its snail intermediate host Biomphalaria glabrata. S. mansoni larval stage ESPs are known to interfere with haemocyte physiology and behaviour. Haemocytes from two different B. glabrata strains, one which is susceptible to S. mansoni infection and one which is resistant, both showed reduced HSP70 protein levels following 1 h challenge with S. mansoni ESPs when compared to unchallenged controls; however, the reduction observed in the resistant strain was less marked. The decline in intracellular HSP70 protein persisted for at least 5 h in resistant snail haemocytes only. Furthermore, in schistosome-susceptible snails infected by S. mansoni for 35 days, haemocytes possessed approximately 70% less HSP70. The proteasome inhibitor, MG132, partially restored HSP70 protein levels in ESP-challenged haemocytes, demonstrating that the decrease in HSP70 was in part due to intracellular degradation. The extracellular signal-regulated kinase (ERK) signalling pathway appears to regulate HSP70 protein expression in these cells, as the mitogen-activated protein-ERK kinase 1/2 (MEK1/2) inhibitor, U0126, significantly reduced HSP70 protein levels. Disruption of intracellular HSP70 protein expression in B. glabrata haemocytes by S. mansoni ESPs may be a strategy employed by the parasite to manipulate the immune response of the intermediate snail host.

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Proteasome Inhibitors MG132 and Lactacystin Hyperphosphorylate HSF1 and Induce hsp70 and hsp27 Expression

Cited by 113 publications

References 23 publications

z-Leucinyl-Leucinyl-Norleucinal Induces Apoptosis of Human Glioblastoma Tumor–Initiating Cells by Proteasome Inhibition and Mitotic Arrest Response

z-Leucinyl-Leucinyl-Norleucinal Induces Apoptosis of Human Glioblastoma Tumor–Initiating Cells by Proteasome Inhibition and Mitotic Arrest Response

Inhibition of proteasome by bortezomib causes intracellular aggregation of hepatic serpins and increases the latent circulating form of antithrombin

Larval excretory-secretory products from the parasite Schistosoma mansoni modulate HSP70 protein expression in defence cells of its snail host, Biomphalaria glabrata

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