Initiation and execution of lipotoxic ER stress in pancreatic β-cells

Cunha, Daniel Andrade Da; Hekerman, Paul; Ladrière, Laurence; Bazarra-Castro, Angie; Ortis, Fernanda; Wakeham, Marion C.; Moore, Fabrice; Rasschaert, Joanne; Cardozo, Alessandra K; Bellomo, Elisa A.; Overbergh, Lutgart; Mathieu, Chantal; Lupi, R; Hai, Tsonwin; Herchuelz, André; Marchetti, Piero; Rutter, Guy A.; Eizirik, Décio L.; Cnop, Miriam

doi:10.1242/jcs.026062

Cited by 534 publications

(693 citation statements)

References 104 publications

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“…These data suggest that increased insulin demand under insulin-resistant conditions produces chronic ER stress in beta cells. In addition, NEFA, which are elevated in these insulin-resistant models, may also contribute to the activation of UPR [32]. In this regard, Lipson et al recently demonstrated that hyperglycaemia activates inositol-requiring protein-1 (IRE1)α, an ER-resident transmembrane protein kinase regulating UPR in beta cells.…”

Section: Discussionmentioning

confidence: 99%

“…In this mouse, ectopically expressed agouti protein promotes food intake and weight gain by antagonising signalling at melanocortin-4 receptor in the hypothalamus. ER stress is likely to have been induced in these beta cells by increased insulin synthesis and secretion demands, and also by elevated serum NEFA [32]. As Wfs1 −/− mice on the C57BL/6J background rarely develop overt diabetes by 24 weeks, we introduced the A y mutation into C57BL/6J Wfs1 −/− mice and assessed the consequences.…”

Section: Introductionmentioning

confidence: 99%

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Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice

et al. 2009

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Aims/hypothesis The WFS1 gene encodes an endoplasmic reticulum (ER) membrane-embedded protein called Wolfram syndrome 1 protein, homozygous mutations of which cause selective beta cell loss in humans. The function(s) of this protein and the mechanism by which the mutations of this gene cause beta cell death are still not fully understood. We hypothesised that increased insulin demand as a result of obesity/insulin resistance causes ER stress in pancreatic beta cells, thereby promoting beta cell death. Methods We studied the effect of breeding Wfs1 −/− mice on a C57BL/6J background with mild obesity and insulin resistance, by introducing the agouti lethal yellow mutation (A y /a). We also treated the mice with pioglitazone.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice

et al. 2009

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“…The preparations used in the present study contained 88.1±4.5% beta cells (n=5). Dispersed islets or FACS-purified beta cells were pre-cultured in complete beta cell medium supplemented with 5% heat-inactivated FBS from 20 to 48 h for recovery [15]. Experiments were then conducted in medium without serum [2,13].…”

Section: Methodsmentioning

confidence: 99%

“…RNA interference Small interference RNA (siRNA) transfection in rat dispersed beta cells was conducted according to a protocol recently developed in our laboratory [15] using DharmaFECT 1 (Termo Scientific, Chicago, IL, USA) with a final concentration of 30 nmol/l siRNA. The efficiency of transfection was >90% [15].…”

Section: Methodsmentioning

confidence: 99%

Sustained production of spliced X-box binding protein 1 (XBP1) induces pancreatic beta cell dysfunction and apoptosis

et al. 2010

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Aims/hypothesis Pro-inflammatory cytokines involved in the pathogenesis of type 1 diabetes deplete endoplasmic reticulum (ER) Ca 2+ stores, leading to ER-stress and beta cell apoptosis. However, the cytokine-induced ER-stress response in beta cells is atypical and characterised by induction of the pro-apoptotic PKR-like ER kinase (PERK)-C/EBP homologous protein (CHOP) branch of the unfolded protein response, but defective X-box binding protein 1 (XBP1) splicing and activating transcription factor 6 activation. The purpose of this study was to overexpress spliced/active Xbp1 (XBP1s) to increase beta cell resistance to cytokine-induced ER-stress and apoptosis.Methods Xbp1s was overexpressed using adenoviruses and knocked down using small interference RNA in rat islet cells. In selected experiments, Xbp1 was also knocked down in FACS-purified rat beta cells and rat fibroblasts. Expression and production of XBP1s and key downstream genes and proteins was measured and beta cell function and viability were evaluated.

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“…Also, chronic exposure to long-chain free fatty acids induces ER stress and cell death in pancreatic beta-cells (Cunha et al, 2008). Synthetic alkyl-lysophospholipid analogs (ALPs) are a novel class of unnatural lipids with promising anticancer activity, including clinically relevant drugs such as miltefosine, perifosine and erucylphosphocholine, which act at the cell membrane level (Gajate and Mollinedo, 2002;Mollinedo et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Antitumor alkyl-lysophospholipid analog edelfosine induces apoptosis in pancreatic cancer by targeting endoplasmic reticulum

et al. 2011

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Pancreatic cancer remains as one of the most deadly cancers, and responds poorly to current therapies. The prognosis is extremely poor, with a 5-year survival of less than 5%. Therefore, search for new effective therapeutic drugs is of pivotal need and urgency to improve treatment of this incurable malignancy. Synthetic alkyl-lysophospholipid analogs (ALPs) constitute a heterogeneous group of unnatural lipids that promote apoptosis in a wide variety of tumor cells. In this study, we found that the anticancer drug edelfosine was the most potent ALP in killing human pancreatic cancer cells, targeting endoplasmic reticulum (ER). Edelfosine was taken up in significant amounts by pancreatic cancer cells and induced caspaseand mitochondrial-mediated apoptosis. Pancreatic cancer cells show a prominent ER and edelfosine accumulated in this subcellular structure, inducing a potent ER stress response, with caspase-4, BAP31 and c-Jun NH 2 -terminal kinase (JNK) activation, CHOP/GADD153 upregulation and phosphorylation of eukaryotic translation initiation factor 2 a-subunit that eventually led to cell death. Oral administration of edelfosine in xenograft mouse models of pancreatic cancer induced a significant regression in tumor growth and an increase in apoptotic index, as assessed by TUNEL assay and caspase-3 activation in the tumor sections. The ER stress-associated marker CHOP/ GADD153 was visualized in the pancreatic tumor isolated from edelfosine-treated mice, indicating a strong in vivo ER stress response. These results suggest that edelfosine exerts its pro-apoptotic action in pancreatic cancer cells, both in vitro and in vivo, through its accumulation in the ER, which leads to ER stress and apoptosis. Thus, we propose that the ER could be a key target in pancreatic cancer, and edelfosine may constitute a prototype for the development of a new class of antitumor drugs targeting the ER.

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Initiation and execution of lipotoxic ER stress in pancreatic β-cells

Cited by 534 publications

References 104 publications

Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice

Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice

Sustained production of spliced X-box binding protein 1 (XBP1) induces pancreatic beta cell dysfunction and apoptosis

Antitumor alkyl-lysophospholipid analog edelfosine induces apoptosis in pancreatic cancer by targeting endoplasmic reticulum

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