Free Fatty Acid Induces Endoplasmic Reticulum Stress and Apoptosis of β-cells by Ca2+/Calpain-2 Pathways

Cui, Wei; Ma, Jie; Wang, Xingqin; Yang, Wenjuan; Zhang, Jing; Ji, Qiuhe

doi:10.1371/journal.pone.0059921

Cited by 72 publications

(49 citation statements)

References 51 publications

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“…Calpain activation has been found to be associated with type 2 diabetes and various neuronal diseases including Alzheimers, traumatic brain injury and cerebral ischemia, suggesting that regulation of calpains is crucial for cellular health (23). We discovered that calpain inhibitor III could confer protection against thapsigargin mediated cell death (Fig.…”

Section: Discussionmentioning

confidence: 91%

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A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome

Kanekura

Hara

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

137

168

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Wolfram syndrome is a genetic disorder characterized by diabetes and neurodegeneration and considered as an endoplasmic reticulum (ER) disease. Despite the underlying importance of ER dysfunction in Wolfram syndrome and the identification of two causative genes, Wolfram syndrome 1 (WFS1) and Wolfram syndrome 2 (WFS2), a molecular mechanism linking the ER to death of neurons and β cells has not been elucidated. Here we implicate calpain 2 in the mechanism of cell death in Wolfram syndrome. Calpain 2 is negatively regulated by WFS2, and elevated activation of calpain 2 by WFS2-knockdown correlates with cell death. Calpain activation is also induced by high cytosolic calcium mediated by the loss of function of WFS1. Calpain hyperactivation is observed in the WFS1 knockout mouse as well as in neural progenitor cells derived from induced pluripotent stem (iPS) cells of Wolfram syndrome patients. A small-scale small-molecule screen targeting ER calcium homeostasis reveals that dantrolene can prevent cell death in neural progenitor cells derived from Wolfram syndrome iPS cells. Our results demonstrate that calpain and the pathway leading its activation provides potential therapeutic targets for Wolfram syndrome and other ER diseases.Wolfram syndrome | endoplasmic reticulum | diabetes | neurodegeneration | treatment

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Section: Discussionmentioning

confidence: 91%

“…1A). Previous studies have shown that calpain 2 activation is regulated on the ER membrane and it plays a role in ER stress-induced apoptosis and β cell death (20,(22)(23)(24), which prompted us to study the role of WFS2 in calpain 2 activation.…”

Section: Significancementioning

confidence: 99%

A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome

Kanekura

Hara

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

137

168

View full text Add to dashboard Cite

show abstract

“…Endoplasmic reticulum (ER) stress has been considered one of the factors to lead to diseases through ER stress-induced apoptosis (Cui et al, 2013;Hamamura and Yokota, 2007). In animal knockout models, GADD153 mediates apoptosis induced by ER stress in pancreatic cells and by ischemic stress induced in brain neuronal cells (Oyadomari et al, 2002;Tajiri et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

PEITC induces apoptosis of Human Brain Glioblastoma GBM8401 Cells through the extrinsic- and intrinsic -signaling pathways

Chou

Chang

Wang

et al. 2015

Neurochemistry International

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Glioblastoma is the most common and most aggressive primary brain malignancy. The multimodality treatments for this tumor including surgery, radiotherapy, and chemotherapy, are still not completely satisfied. Phenethyl isothiocyanate (PEITC), one member of the isothiocyanate family, has been shown to induce apoptosis in many human cancer cells. In this study, we investigate the pro-apoptotic effects caused by PETIC in human brain glioblastoma multiforme GBM 8401 cells. In our data, PEITC induced the cell morphological changes and decreased the cell viability of GBM8401 cells in a dose- and time-dependent manner. Moreover, the analysis of cell cycle distribution detected by flow cytometry showed that PEITC induced significantly sub-G1 phase (apoptotic population) in GBM 8401 cells. In addition, PEITC promoted the production of reactive oxygen species (ROS) and increase in [Ca2+]I, but decreased the mitochondrial membrane potential (ΔΨm) in treated cells. PEITC also induced caspases activities in GBM 8401 cells. Results from Western blot analysis indicated that PEITC promoted Fas, FasL, FADD, TRAIL, caspase-8, -9, -3, increased the pro-apoptotic protein (Bax, Bid and Bak), and inhibited the anti-apoptotic proteins (Bcl-2 and Bcl-xl) in GBM 8401 cells. Furthermore, PEITC promoted the release of cytochrome c, AIF and Endo G. GADD153, GRP 78, XBP-1 and IRE-1α, Calpain I and II in GBM 8401 cells. PEITC also promoted the expression of associated protein with endoplasmic reticulum (ER) stress. PEITC induces apoptosis through the extrinsic (death receptor) pathway, dysfunction of mitochondria, ROS induced ER stress, intrinsic (mitochondrial) pathway in GBM 8401 cells. The possible molecular mechanisms and signaling pathways of the anti-cancer properties of PEITC for human brain glioblastoma cells were postulated.

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“…Saturated fatty acids such as palmitate induce ER stress, whereas unsaturated fatty acids exert protective effects; in INS1 cells, palmitate activated UPR via the PERK and IRE1 pathways, and the effect was prevented by co-treatment with oleate [65]. In bTC3 cells, palmitate activated all three UPR pathways, through store-activated calcium entry [66]. Palmitate also induced ER stress in a human beta cell line [67].…”

Section: Intracellular Mechanisms Of Lipotoxicitymentioning

confidence: 99%

Lipotoxicity in the Pancreatic Beta Cell: Not Just Survival and Function, but Proliferation as Well?

2014

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Free fatty acids (FFAs) exert both positive and negative effects on beta cell survival and insulin secretory function, depending on concentration, duration, and glucose abundance. Lipid signals are mediated not only through metabolic pathways, but also through cell surface and nuclear receptors. Toxicity is modulated by positive signals arising from circulating factors such as hormones, growth factors and incretins, as well as negative signals such as inflammatory mediators and cytokines. Intracellular mechanisms of lipotoxicity include metabolic interference and cellular stress responses such as oxidative stress, endoplasmic reticulum (ER) stress, and possibly autophagy. New findings strengthen an old hypothesis that lipids may also impair compensatory beta cell proliferation. Clinical observations continue to support a role for lipid biology in the risk and progression of both type 1 (T1D) and type 2 diabetes (T2D). This review summarizes recent work in this important, rapidly evolving field.

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Free Fatty Acid Induces Endoplasmic Reticulum Stress and Apoptosis of β-cells by Ca2+/Calpain-2 Pathways

Cited by 72 publications

References 51 publications

A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome

A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome

PEITC induces apoptosis of Human Brain Glioblastoma GBM8401 Cells through the extrinsic- and intrinsic -signaling pathways

Lipotoxicity in the Pancreatic Beta Cell: Not Just Survival and Function, but Proliferation as Well?

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