Hexapeptide-11 is a novel modulator of the proteostasis network in human diploid fibroblasts

Sklirou, Aimilia D.; Ralli, Marianna; Domı́nguez, Marı́a; Papassideri, Issidora S.; Skaltsounis, Alexios‐Léandros; Trougakos, Ioannis P.

doi:10.1016/j.redox.2015.04.010

Cited by 28 publications

(25 citation statements)

References 44 publications

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“…The cytotoxic effect of PIs against the MM cell lines was determined by using the MTT reagent (Sigma‐Aldrich). The proteasome activities were measured as described before . For details, see also Supporting Information.…”

Section: Methodsmentioning

confidence: 99%

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Non‐lethal proteasome inhibition activates pro‐tumorigenic pathways in multiple myeloma cells

Skorda

Sklirou

Sakellaropoulos

et al. 2019

J Cellular Molecular Medi

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Multiple myeloma (MM) is a haematological malignancy being characterized by clonal plasma cell proliferation in the bone marrow. Targeting the proteasome with specific inhibitors (PIs) has been proven a promising therapeutic strategy and PIs have been approved for the treatment of MM and mantle‐cell lymphoma; yet, while outcome has improved, most patients inevitably relapse. As relapse refers to MM cells that survive therapy, we sought to identify the molecular responses induced in MM cells after non‐lethal proteasome inhibition. By using bortezomib (BTZ), epoxomicin (EPOX; a carfilzomib‐like PI) and three PIs, namely Rub999, PR671A and Rub1024 that target each of the three proteasome peptidases, we found that only BTZ and EPOX are toxic in MM cells at low concentrations. Phosphoproteomic profiling after treatment of MM cells with non‐lethal (IC10) doses of the PIs revealed inhibitor‐ and cell type‐specific readouts, being marked by the activation of tumorigenic STAT3 and STAT6. Consistently, cytokine/chemokine profiling revealed the increased secretion of immunosuppressive pro‐tumorigenic cytokines (IL6 and IL8), along with the inhibition of potent T cell chemoattractant chemokines (CXCL10). These findings indicate that MM cells that survive treatment with therapeutic PIs shape a pro‐tumorigenic immunosuppressive cellular and secretory bone marrow microenvironment that enables malignancy to relapse.

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Section: Methodsmentioning

confidence: 99%

“…The proteasome activities were measured as described before. 18 For details, see also Supporting Information.…”

Section: Cell Viability and Measurement Of Proteasome Peptidase Actmentioning

confidence: 99%

Non‐lethal proteasome inhibition activates pro‐tumorigenic pathways in multiple myeloma cells

Skorda

Sklirou

Sakellaropoulos

et al. 2019

J Cellular Molecular Medi

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“…Proteasome peptidase activities in human skin fibroblasts were measured at a VersaFluor TM Fluorometer System (Bio-Rad laboratories, Hercules, CA, USA) as described previously 64 by using the Boc-Leu-Arg-Arg-AMC-LRR (trypsin-like activity, T-L), Z-Leu-Leu-Glu-AMC-LLE (caspase-like activity, C-L) and Suc-Leu-Leu-Val-Tyr-AMC-LLVY (chymotrypsin-like activity, CT-L) (Enzo Life Sciences, Inc. Farmingdale, NY, USA) fluoropeptides.…”

Section: Methodsmentioning

confidence: 99%

“…Immunoblotting was done as described previously 64 . Briefly, equal total protein μg per sample were separated by SDS-PAGE and blotted onto a nitrocellulose membrane (Immobilion-P, Millipore, Eschborn, Germany); primary and horseradish peroxidase-conjugated secondary antibodies were applied for 1 hr at room temperature and immunoblots were developed by an enhanced chemiluminescence reagent kit (Santa Cruz Biotechnology).…”

Section: Methodsmentioning

confidence: 99%

6-bromo-indirubin-3′-oxime (6BIO), a Glycogen synthase kinase-3β inhibitor, activates cytoprotective cellular modules and suppresses cellular senescence-mediated biomolecular damage in human fibroblasts

Sklirou

Gaboriaud‐Kolar

Papassideri

et al. 2017

Sci Rep

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As genetic interventions or extended caloric restriction cannot be applied in humans, many studies have been devoted to the identification of natural products that can prolong healthspan. 6-bromoindirubin-3′-oxime (6BIO), a hemi-synthetic derivative of indirubins found in edible mollusks and plants, is a potent inhibitor of Glycogen synthase kinase 3β (Gsk-3β). This pleiotropic kinase has been implicated in various age-related diseases including tumorigenesis, neurodegeneration and diabetes. Accordingly, 6BIO has shown anti-tumor and anti-neurodegenerative activities; nevertheless, the potential role of 6BIO in normal human cells senescence remains largely unknown. We report herein that treatment of human diploid skin fibroblasts with 6BIO reduced the oxidative load, conferred protection against oxidative stress-mediated DNA damage, and it also promoted the activation of antioxidant and proteostatic modules; these effects were largely phenocopied by genetic inhibition of Gsk-3. Furthermore, prolonged treatment of cells with 6BIO, although it decreased the rate of cell cycling, it significantly suppressed cellular senescence-related accumulation of biomolecular damage. Taken together, our presented findings suggest that 6BIO is a novel activator of antioxidant responses and of the proteostasis network in normal human cells; moreover, and given the low levels of biomolecules damage in 6BIO treated senescing cells, this compound likely exerts anti-tumor properties.

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“…Detection was performed with the Pico Plus 158 system (34580, Thermo Scientific) and X-ray films (47410 19284, Fujufilm). Cell-based proteasome activity assays 179 Measurement of proteasome peptidase activities following cell exposure to the compounds was 180 performed as described previously (Sklirou et al, 2015). Briefly, cells were plated in 60 mm dishes, 181 left to adhere overnight and then treated with the test compounds for 24 or 48 h. The cells were then 182 lysed and proteasome activities were assayed as described above.…”

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confidence: 99%

Inhibition of jasmonate-mediated plant defences by the fungal metabolite higginsianin B

Dallery

Zimmer

Halder

et al. 2019

Preprint

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24Infection of Arabidopsis thaliana by the ascomycete fungus Colletotrichum higginsianum is 25 characterised by an early symptomless biotrophic phase followed by a destructive necrotrophic phase. 26 The fungal genome contains 77 secondary metabolism-related biosynthetic gene clusters (BGCs), and 27 their expression during the infection process is tightly regulated. Deleting CclA, a chromatin regulator 28 involved in repression of some BGCs through H3K4 trimethylation, allowed overproduction of 3 29 families of terpenoids and isolation of 12 different molecules. These natural products were tested in 30 combination with methyl jasmonate (MeJA), an elicitor of jasmonate responses, for their capacity to 31 alter defence gene induction in Arabidopsis. Higginsianin B inhibited MeJA-triggered expression of 32 the defence reporter VSP1p:GUS, suggesting it may block bioactive JA-Ile synthesis or signalling in 33 planta. Using the JA-Ile sensor Jas9-VENUS, we found that higginsianin B, but not three other 34 structurally-related molecules, suppressed JA-Ile signalling by preventing degradation of JAZ 35 proteins, the repressors of JA responses. Higginsianin B likely blocks the 26S proteasome-dependent 36 degradation of JAZ proteins because it inhibited chymotrypsin-and caspase-like protease activities. 37 The inhibition of target degradation by higginsianin B also extended to auxin signalling, as 38 higginsianin B treatment reduced IAA-dependent expression of DR5p:GUS. Overall, our data indicate 39 that specific fungal secondary metabolites can act similarly to protein effectors to subvert plant 40 immune and developmental responses.41 Keywords: Colletotrichum; fungal natural product; higginsianin; jasmonate signalling; JAZ protein; plant 42 chemical biology; plant immunity; proteasome; secondary metabolite 43 65 (Dallery et al., 2017). Remarkably, no fewer than 14 BGCs are specifically induced early, during 66 penetration and biotrophic colonization, whereas only five are preferentially activated during 67 necrotrophy. Hence, not including possible biosynthetic intermediates, up to 14 different secondary 68 metabolites are potentially delivered to the first infected host cell, where they may contribute to 69 4establishing a biotrophic interaction with A. thaliana. The transient production of these fungal 70 metabolites exclusively in planta presents a major challenge to their structural characterization and 71 functional analysis. In the past decade, deleting proteins involved in shaping the chromatin landscape 72 has allowed the isolation of numerous novel metabolites from diverse axenically grown fungi (e.g. et al., 2009, Fan et al., 2017, Studt et al., 2016, Wu et al., 2016. Recently, we reported a cclA 74 mutant of C. higginsianum affected in the trimethylation of histone proteins at H3K4 residues which 75 overproduces 12 different metabolites belonging to three terpenoid families, including five new 76 molecules (Dallery et al., 2019a, Dallery et al., 2019b). 77 Despite the huge efforts made in recent years to ch...

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Hexapeptide-11 is a novel modulator of the proteostasis network in human diploid fibroblasts

Cited by 28 publications

References 44 publications

Non‐lethal proteasome inhibition activates pro‐tumorigenic pathways in multiple myeloma cells

Non‐lethal proteasome inhibition activates pro‐tumorigenic pathways in multiple myeloma cells

6-bromo-indirubin-3′-oxime (6BIO), a Glycogen synthase kinase-3β inhibitor, activates cytoprotective cellular modules and suppresses cellular senescence-mediated biomolecular damage in human fibroblasts

Inhibition of jasmonate-mediated plant defences by the fungal metabolite higginsianin B

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