Proteasome inhibition by MG-132 induces apoptotic cell death and mitochondrial dysfunction in cultured rat brain oligodendrocytes but not in astrocytes

Glia ◽  
2006 ◽  
Vol 53 (8) ◽  
pp. 891-901 ◽  
Author(s):  
Olaf Goldbaum ◽  
Grit Vollmer ◽  
Christiane Richter-Landsberg
Keyword(s):  
Cell Death ◽  
Mitochondrial Dysfunction ◽  
Rat Brain ◽  
Apoptotic Cell ◽  
Proteasome Inhibition ◽  
Apoptotic Cell Death

Mitochondrial dysfunction: A crucial event in okadaic acid (ICV) induced memory impairment and apoptotic cell death in rat brain

2011 ◽  
Vol 100 (2) ◽  
pp. 311-319 ◽  
Author(s):  
Pradeep K. Kamat ◽  
Santoshkumar Tota ◽  
Rakesh Shukla ◽  
Shakir Ali ◽  
Abul Kalam Najmi ◽  
...  
Keyword(s):  
Cell Death ◽  
Mitochondrial Dysfunction ◽  
Rat Brain ◽  
Okadaic Acid ◽  
Memory Impairment ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death

scholarly journals Effect of Transient Maternal Hypotension on Apoptotic Cell Death in Foetal Rat Brain

2014 ◽  
Vol 33 (1) ◽  
pp. 88-94
Author(s):  
Hamit Ozyurek ◽  
Sibel Bayrak ◽  
Bilge Pehlivanoglu ◽  
Pergin Atilla ◽  
Zeynep Dicle Balkanci ◽  
...  
Keyword(s):  
Cell Death ◽  
Rat Brain ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Foetal Rat

scholarly journals N-Methyl-D-aspartate antagonists and apoptotic cell death triggered by head trauma in developing rat brain

1999 ◽  
Vol 96 (5) ◽  
pp. 2508-2513 ◽  
Author(s):  
D. Pohl ◽  
P. Bittigau ◽  
M. J. Ishimaru ◽  
D. Stadthaus ◽  
C. Hubner ◽  
...  
Keyword(s):  
Cell Death ◽  
Rat Brain ◽  
Head Trauma ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Developing Rat

scholarly journals Heteronemin, a spongean sesterterpene, inhibits TNFα-induced NF-κB activation through proteasome inhibition and induces apoptotic cell death

2010 ◽  
Vol 79 (4) ◽  
pp. 610-622 ◽  
Author(s):  
Marc Schumacher ◽  
Claudia Cerella ◽  
Serge Eifes ◽  
Sébastien Chateauvieux ◽  
Franck Morceau ◽  
...  
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
Proteasome Inhibition ◽  
Apoptotic Cell Death

Lipopolysaccharide-induced fever is dissociated from apoptotic cell death in the rat brain

1998 ◽  
Vol 805 (1-2) ◽  
pp. 95-103 ◽  
Author(s):  
Abdeslam Mouihate ◽  
Quentin J Pittman
Keyword(s):  
Cell Death ◽  
Rat Brain ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death

scholarly journals Identification of Beta-Catenin As a Novel Ubiquitin-Regulated Target of Combined Flβ3/Syk- and Proteasome Inhibitors for Interruption of LSC Signaling in Poor-Risk AML

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3949-3949
Author(s):  
Sravanti Rangaraju ◽  
Silvia Marino ◽  
Daniela Nicoleta Petrusca ◽  
Larry D Cripe ◽  
Katie J Sargent ◽  
...  
Keyword(s):  
Cell Death ◽  
Wnt Pathway ◽  
Apoptotic Cell ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Apoptotic Cell Death ◽  
Beta Catenin ◽  
Poor Risk ◽  
Syk Inhibitor ◽  
Molecular Phenotypes

Abstract Enhanced blast clearance/remission followed for relapsed/refractory AML patients, in whose blasts were annotated by mutant Flt3 in company with additional TET2 mutation, when a combination of Sorafenib/Vorinostat was supplemented by Bortezomib (Sayar, et al. Oncotarget, 2018). Pharmacodynamic analysis of day0/4 marrow blasts demonstrated early inhibition of HOXA9/10, and/or MEIS1, which occurred upon re-regulation of Wnt pathway participants whose activity had been affected by mTET2. We hypothesized Wnt effectors which drive HOXA overexpression enlist β-Catenin-dependent transactivation of HOXA (Bei, Eklund et al. JBC, 2012), and the role of Bortezomib extends beyond previously recognized AML-specific targets: Flt3ITD, p52NFκB. Therefore a series of primary AML blasts chosen across a spectrum of cytogenetic and molecular categories were analyzed herein to examine the hypothesis that proteasome inhibitors (PI) provide novel targeting action in combination with a new Flt3/Syk inhibitor (FSI) currently in clinical trial, TAK-659 (K Pratz, Blood(abstract) 2018) or, alternatively, when using a previously-reported compound with similar FSI selectivity, R406 (Puissant, Stegmaier, et al. Cancer Cell, 2014). Either of these agents alone or in combination with Bortezomib or Ixazomib were tested to learn respective mechanism of action, and to identify sensitive molecular phenotypes. In order to study β-Catenin as target, we incubated AML blasts in culture with the following treatments: control, FSI, PI, or PI+FSI, while using informative dosing in tandem cultures for proliferation, apoptosis, gene expression and proteomic endpoints. Because ubiquitination directs substrate proteolysis as well as subcellular localization for transcriptional regulators, we isolated within each test group both cytoplasmic and nuclear protein. Also, because activity of β-Catenin involves phosphorylation-initiated and ubiquitin-directed trafficking, we probed immunoblots for both nonphosphorylated [active] (S33,S37,T41)- and phosphorylated β-Catenin species. For Flt3/Syk inhibition by TAK-659, we used concentrations at, and below, a clinically-achievable optimal concentration of 250 nM (opcit). In all cases of Flt3mutant AML's studied, we observed synergy between Flt3/Syk inhibitor with PI, including at clinically suboptimal concentrations of individual agents. This cooperative activity involved loss of active, nonphosphorylated β-Catenin (80kD) from the nucleus, and the cytoplasmic accumulation of large ubiquitin-laden species of phospho-β-Catenin, ranging from 100-175kD, under conditions where apoptotic cell death occurred. A cytoplasmically-localized gatekeeper for stopping canonical Wnt pathway activation, Axin1, was not limiting for the loss of nuclear β-Catenin by the combination: FSI plus PI, but was modestly upregulated by PI alone. However, nuclear-localized FOXM1, a known nuclear chaperone for β-Catenin, was frequently significantly reduced by PI or the combination of FSI/PI. Both Flt3ITD (cytoplasmic) and p52NFκB (nuclear) were lost in additive fashion by combination treatments. At the transcriptional level (real-time RT-PCR), c-jun (a transactivator for FOXM1 and CTNNB1), Syk, as well as FOXM1, HOXA and MEIS1 were additively repressed by combination FSI plus PI in select AML blasts. Certain AML molecular phenotypes demonstrated heightened sensitivity to the combination of TAK-659 plus PIs. Within blasts bearing hierarchically-related mutant effectors: IDH2, TET2, or WT1-all recognized to dampen Wnt-inhibitory pathways, we observed that the combination of TAK-659 with PI was cooperatively active in both Flt3mutant and Flt3wild-type AMLs, while accompanied by an inhibitory effect on β-Catenin. In summary, proteasome inhibition with Ixazomib or Bortezomib cooperated with Flt3/Syk inhibition to cause apoptotic cell death in both Flt3mutant and wild-type AML's with Wnt pathway DNA/chromatin modifying enzyme mutations, a process which appeared to depend upon loss of nuclear-active β-Catenin and FOXM1, and accompanied by accumulation of large, ubiquitin-laden cytoplasmic β-Catenin species. Thus, proteasome inhibition in combination with inhibition of Flt3/Syk holds a central role in targeted therapy of certain poor-risk de novo AMLs, by interdiction of a leukemic stem cell (LSC) signature and causing apoptosis of AML blasts. Disclosures Roodman: Amgen Denosumab: Membership on an entity's Board of Directors or advisory committees.

Sign in / Sign up

Export Citation Format

Share Document