Activation of NFκB dependent apoptotic pathway in pancreatic islet cells by hypoxia

Lai, Yi; Brandhorst, Heide; Hossain, Hamid; Bierhaus, Angelika; Chen, Chunguang; Bretzel, Reinhard G.; Linn, Thomas

doi:10.4161/isl.1.1.8530

Cited by 23 publications

(29 citation statements)

References 27 publications

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“…A strong correlation between reduced oxygen supply and the occurrence of beta cell apoptosis in isolated human and rat islets was shown previously (Moritz et al 2002;Lai et al 2009). In intact rodent islet, non-beta cells comprise about 20% of the total cell population and glucagon-producing alpha cells being the most abundant (Orci and Unger 1975;Elayat et al 1995).…”

Section: Beta Cell and Alpha Cell Apoptosis Induced By Hypoxiamentioning

confidence: 87%

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Different susceptibility of rat pancreatic alpha and beta cells to hypoxia

Bloch

Vennäng

Lazard

et al. 2012

Histochem Cell Biol

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Insulin-producing beta cells are known to be highly susceptible to hypoxia, which is a major factor in their destruction after pancreatic islet transplantation. However, whether the glucagon-producing pancreatic islet alpha cells are sensitive to hypoxia is not known. Our objective was to compare the sensitivity of alpha and beta cells to hypoxia. Isolated rat pancreatic islets were exposed to hypoxia (1% oxygen, 94% N(2), 5% CO(2)) for 3 days. The viability of the alpha and beta cells, as well as the stimulus-specific secretion of glucagon and insulin, was evaluated. A quantitative analysis of the proportion of beta to alpha cells indicated that, under normoxic conditions, islet cells were composed mainly of beta cells (87 ± 3%) with only 13 ± 3% alpha cells. Instead, hypoxia treatment significantly increased the proportion of alpha cells (40 ± 13%) and decreased the proportion of beta cells to 60 ± 13%. Using the fluorescent TUNEL assay we found that only a few percent of beta cells and alpha cells were apoptotic in normoxia. In contrast, hypoxia induced an abundance of apoptotic beta cells (61 ± 22%) and had no effect on the level of apoptosis in alpha cells. In conclusion, this study demonstrates that hypoxia results in severe functional abnormality in both beta and alpha cells while alpha cells display significantly decreased rate of apoptosis compared to intensive apoptotic injury of beta cells. These findings have implications for the understanding of the possible role of hypoxia in the pathophysiology of diabetes.

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Section: Beta Cell and Alpha Cell Apoptosis Induced By Hypoxiamentioning

confidence: 87%

“…Low beta cell survival and abnormal insulin release from pancreatic beta cells exposed to hypoxia have been extensively studied and found in different mammalian species (Dionne et al 1993;Moritz et al 2002;Lai et al 2009). Fig.…”

Section: Discussionmentioning

confidence: 99%

Different susceptibility of rat pancreatic alpha and beta cells to hypoxia

Bloch

Vennäng

Lazard

et al. 2012

Histochem Cell Biol

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“…This is well-illustrated by our model 15, 39 calculated values shown in Supplementary Figure S8. While tissue oxygen concentrations are around 5% 21, 22 , most of the islet tissue will be exposed to lower oxygen concentrations, hence 3% is a reasonable choice and one that has been used by others 33, 34 . For hypoxic islets, levels of N -formylmethionine, an amino acid used for initiation of mitochondrial protein synthesis 72 , were significantly decreased, indicating β-cell death and stress 73, 74 .…”

Section: Discussionmentioning

confidence: 99%

Metabolomics Study of the Effects of Inflammation, Hypoxia, and High Glucose on Isolated Human Pancreatic Islets

et al. 2017

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The transplantation of human pancreatic islets is a therapeutic possibility for a subset of type 1 diabetic patients who experience severe hypoglycemia. Pre- and post-transplantation loss in islet viability and function, however, is a major efficacy-limiting impediment. To investigate the effects of inflammation and hypoxia, the main obstacles hampering the survival and function of isolated, cultured, and transplanted islets, we conducted a comprehensive metabolomics evaluation of human islets in parallel with dynamic glucose-stimulated insulin release (GSIR) perifusion studies for functional evaluation. Metabolomics profiling of media and cell samples identified a total of 241 and 361 biochemicals, respectively. Metabolites that were altered in highly significant manner in both included, for example, kynurenine, kynurenate, citrulline, and mannitol/sorbitol under inflammation (all elevated) plus lactate (elevated) and N-formylmethionine (depressed) for hypoxia. Dynamic GSIR experiments, which capture both first- and second-phase insulin release, found severely depressed insulin-secretion under hypoxia, whereas elevated baseline and stimulated insulin-secretion was measured for islet exposed to the inflammatory cytokine cocktail (IL-1β, IFN-γ, and TNF-α). Because of the uniquely large changes observed in kynurenine and kynurenate, they might serve as potential biomarkers of islet inflammation, and IDO on the corresponding pathway could be a worthwhile therapeutic target to dampen inflammatory effects.

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“…The regulation of Mcl-1 by hypoxia thus seems cell type dependent. There are reports that hypoxia can increase NF-κB signaling (34,35) and that activation of NF-κB can upregulate Mcl-1 levels (36), which would drive resistance to ABT-737. Although NF-κB was not explored in this study, the reduced expression of Mcl-1 in hypoxia in SCLC and CRC cells would suggest that this pathway, if operational, is overridden.…”

Section: Discussionmentioning

confidence: 99%

Hypoxic human cancer cells are sensitized to BH-3 mimetic–induced apoptosis via downregulation of the Bcl-2 protein Mcl-1

Harrison

Micha²,

Brandenburg³

et al. 2011

J. Clin. Invest.

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Solid tumors contain hypoxic regions in which cancer cells are often resistant to chemotherapy-induced apoptotic cell death. Therapeutic strategies that specifically target hypoxic cells and promote apoptosis are particularly appealing, as few normal tissues experience hypoxia. We have found that the compound ABT-737, a Bcl-2 homology domain 3 (BH-3) mimetic, promotes apoptotic cell death in human colorectal carcinoma and small cell lung cancer cell lines exposed to hypoxia. This hypoxic induction of apoptosis was mediated through downregulation of myeloid cell leukemia sequence 1 (Mcl-1), a Bcl-2 family protein that serves as a biomarker for ABT-737 resistance. Downregulation of Mcl-1 in hypoxia was independent of hypoxia-inducible factor 1 (HIF-1) activity and was consistent with decreased global protein translation. In addition, ABT-737 induced apoptosis deep within tumor spheroids, consistent with an optimal hypoxic oxygen tension being necessary to promote ABT-737-induced cell death. Tumor xenografts in ABT-737-treated mice also displayed significantly more apoptotic cells within hypoxic regions relative to normoxic regions. Synergies between ABT-737 and other cytotoxic drugs were maintained in hypoxia, suggesting that this drug may be useful in combination with chemotherapeutic agents. Taken together, these findings suggest that Mcl-1-sparing BH-3 mimetics may induce apoptosis in hypoxic tumor cells that are resistant to other chemotherapeutic agents and may have a role in combinatorial chemotherapeutic regimens for treatment of solid tumors.

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Activation of NFκB dependent apoptotic pathway in pancreatic islet cells by hypoxia

Cited by 23 publications

References 27 publications

Different susceptibility of rat pancreatic alpha and beta cells to hypoxia

Different susceptibility of rat pancreatic alpha and beta cells to hypoxia

Metabolomics Study of the Effects of Inflammation, Hypoxia, and High Glucose on Isolated Human Pancreatic Islets

Hypoxic human cancer cells are sensitized to BH-3 mimetic–induced apoptosis via downregulation of the Bcl-2 protein Mcl-1

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