Coupling endoplasmic reticulum stress to cell death program in isolated human pancreatic islets: effects of gene transfer of Bcl-2

Contreras, Juan L.; Smyth, Cheryl A.; Bilbao, Guadalupe; Eckstein, Christopher; Young, Carlton J.; Thompson, John A.; Curiel, David T.; Eckhoff, Devin E.

doi:10.1007/s00147-003-0619-x

Cited by 18 publications

(15 citation statements)

References 22 publications

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“…on March 27, 2019. by guest www.bloodjournal.org From overexpression of antiapoptotic proteins by gene transfer has been shown to reduce sensitivity to BFA in cell culture systems. 76,77 The fact that we did not observe a correlation between high antiapoptotic protein expression and reduced sensitivity to BFA in this study could be due to a difference between endogenous expression levels and those achieved by gene transfer, or due to the functional effect of these proteins in different cellular contexts.…”

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confidence: 39%

Targeting endoplasmic reticulum protein transport: a novel strategy to kill malignant B cells and overcome fludarabine resistance in CLL

Carew

Nawrocki

Krupnik

et al. 2006

Blood

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Previous studies showed that chronic lymphocytic leukemia (CLL) cells exhibit certain mitochondrial abnormalities including mtDNA mutations, increased superoxide generation, and aberrant mitochondrial biogenesis, which are associated with impaired apoptosis and reduced sensitivity to fludarabine. Here we report that CLL cells and multiple myeloma cells are highly sensitive to brefeldin A, an inhibitor of endoplasmic reticulum (ER) to Golgi protein transport currently being developed as a novel anticancer agent in a prodrug formulation. Of importance, brefeldin A effectively induced apoptosis in fludarabine-refractory CLL cells. Disruption of protein trafficking by brefeldin A caused the sequestration of the prosurvival factors APRIL and VEGF in the ER, leading to abnormal ER swelling and a decrease in VEGF secretion. Such ER stress and blockage of secretory protein traffic eventually resulted in Golgi collapse, activation of caspases, and cell death. Notably, the cellular sensitivity to this compound appeared to be independent of p53 status. Taken together, these findings suggest that malignant B cells may be highly dependent on ER-Golgi protein transport and that targeting this process may be a promising therapeutic strategy for B-cell malignancies, especially for those that respond poorly to conventional treatments. IntroductionChronic lymphocytic leukemia (CLL) is a common adult leukemia with unique characteristics in that the disease progression involves the persistent accumulation of apparently quiescent B cells, primarily due to defects in apoptosis rather than increased cell proliferation. 1 The apoptotic resistance of CLL cells has been attributed, in part, to high expression of antiapoptotic proteins such as Bcl-2, Bcl-X L , and Mcl-1. [2][3][4][5][6][7][8] Our previous work demonstrated that CLL cells contain multiple mitochondrial defects including mtDNA mutations, aberrant mitochondrial biogenesis, and increased generation of the oxygen radical superoxide, which is predominantly produced in the mitochondria. These abnormalities are associated with alterations in sensitivity to anticancer agents, suggesting that they may compromise the execution of the mitochondrial apoptotic machinery. [9][10][11] Fludarabine and alkylating agents have significantly improved clinical outcomes of CLL treatment. However, there are currently limited effective therapeutic options for patients that are refractory to these agents. 1,12,13 Thus, identification and evaluation of novel agents for the treatment of refractory CLL are important and challenging tasks. While investigating the mechanistic basis of aberrant mitochondrial biogenesis activity in primary CLL cells, we observed that in addition to increased mitochondrial content, CLL cells also appear to have a more extensive endoplasmic reticulum (ER) network than normal B lymphocytes. 10 The abundance of ER membranes in CLL cells has also been noted in earlier investigations and suggests that ER function may be very important for their survival. Consequently, this or...

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confidence: 39%

Targeting endoplasmic reticulum protein transport: a novel strategy to kill malignant B cells and overcome fludarabine resistance in CLL

Carew

Nawrocki

Krupnik

et al. 2006

Blood

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“…The endoplasmic reticulum is the major signal transducing cellular organelle that continuously responds to environmental cues to release calcium and is sensitive to alterations in calcium homeostasis (Contreras et al 2003) or to the exposure to free radicals (Yoneda et al 2001). Perturbations of steady state Ca 2+ levels in the endoplasmic reticulum can be apoptogenic and the inhibition of the sarko/endoplasmic calcium ATPase (SERCA) by thapsigargin induces apoptosis (Ferri and Kroemer 2001) and the activation of caspase 12 (Jimbo et al 2003).…”

Section: Discussionmentioning

confidence: 99%

Cyclic AMP alleviates endoplasmic stress and programmed cell death induced by lipopolysaccharides in human endothelial cells

et al. 2005

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The possible protection provided by enhancement of the cAMP signal in the process of lipopolysaccharide (LPS)-induced endothelial cell death has been addressed, with special emphasis on the endoplasmic initiation of caspase-12-mediated apoptosis. Human umbilical vein endothelial cells were challenged with LPS to reduce viability after 12 h to less than 20% that of the control. Cell death was preceded by ultrastructural disintegration at the endoplasmic reticulum, PERK-phosphorylation, degradation of caspase-12-like protein and cleavage of caspase 9, resulting in apoptosis through the activation of caspase 3. Treatment with a cell-permeable cAMP analogue led to a dose-dependent reduction of cell death over time, mitigated endoplasmic reticulum disturbances, reduced phosphorylation of PERK, and the degradation of caspases 12, 9 and 3. The selective inhibition of caspase 9 completely supplanted the anti-apoptotic effects obtained by cAMP, while being without any influence on caspase 12 degradation. The data suggest that cAMP positively modulates early endoplasmic alterations and caspase activation in LPS-induced apoptosis.

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“…b-cell apoptosis ensues from strong prolonged triggers for ER stress in vitro including exposure to chemicals that directly cause protein misfolding such as tunicamycin (inhibitor of N-glycosylation in the ER) and thapsigargin (disturbs SERCA-mediated Ca 2C retention in the ER) or environmental factors such as cytokines and glucolipotoxicity (Oyadomari et al 2002, Contreras et al 2003, Cardozo et al 2005, Endo et al 2006, Ito et al 2006, Cunha et al 2008, Papa 2012, Yang et al 2013. There are several mechanisms by which UPR signalling that is above a threshold drives b-cell apoptosis with the most important being PERK/ATF4-mediated activation of CHOP and IRE1a/TRAF2/ASK1-mediated activation of JNK (reviewed in Papa (2012)).…”

Section: Intrinsic Er Functionsmentioning

confidence: 99%

Oxidative and endoplasmic reticulum stress in β-cell dysfunction in diabetes

Hasnain¹,

Prins²,

McGuckin³

2015

Journal of Molecular Endocrinology

226

180

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The inability of pancreatic b-cells to make sufficient insulin to control blood sugar is a central feature of the aetiology of most forms of diabetes. In this review we focus on the deleterious effects of oxidative stress and endoplasmic reticulum (ER) stress on b-cell insulin biosynthesis and secretion and on inflammatory signalling and apoptosis with a particular emphasis on type 2 diabetes (T2D). We argue that oxidative stress and ER stress are closely entwined phenomena fundamentally involved in b-cell dysfunction by direct effects on insulin biosynthesis and due to consequences of the ER stress-induced unfolded protein response. We summarise evidence that, although these phenomenon can be driven by intrinsic b-cell defects in rare forms of diabetes, in T2D b-cell stress is driven by a range of local environmental factors including increased drivers of insulin biosynthesis, glucolipotoxicity and inflammatory cytokines. We describe our recent findings that a range of inflammatory cytokines contribute to b-cell stress in diabetes and our discovery that interleukin 22 protects b-cells from oxidative stress regardless of the environmental triggers and can correct much of diabetes pathophysiology in animal models. Finally we summarise evidence that b-cell dysfunction is reversible in T2D and discuss therapeutic opportunities for relieving oxidative and ER stress and restoring glycaemic control.

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Coupling endoplasmic reticulum stress to cell death program in isolated human pancreatic islets: effects of gene transfer of Bcl-2

Cited by 18 publications

References 22 publications

Targeting endoplasmic reticulum protein transport: a novel strategy to kill malignant B cells and overcome fludarabine resistance in CLL

Targeting endoplasmic reticulum protein transport: a novel strategy to kill malignant B cells and overcome fludarabine resistance in CLL

Cyclic AMP alleviates endoplasmic stress and programmed cell death induced by lipopolysaccharides in human endothelial cells

Oxidative and endoplasmic reticulum stress in β-cell dysfunction in diabetes

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