Synergistic activation of JNK/SAPK induced by TNF-α and IFN-γ: Apoptosis of pancreatic β-cells via the p53 and ROS pathway

Kim, Won‐Ho; Lee, June Woo; Gao, Bin; Jung, Myeong Ho

doi:10.1016/j.cellsig.2005.03.020

Cited by 99 publications

(77 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The role of p53 in ␤-cells has been poorly investigated. The p53 signaling pathway has been shown to be activated by cytokines (37) and to potentiate FFA-induced apoptosis in insulinoma cell lines (38). Our data show that the p53 pathway is activated with chronic exposure to FFAs and identify the rise of miR34a as an additional mechanism through which p53 can trigger apoptosis in ␤-cells.…”

Section: Diabetes Vol 57 October 2008mentioning

confidence: 60%

Alterations in MicroRNA Expression Contribute to Fatty Acid–Induced Pancreatic β-Cell Dysfunction

et al. 2008

View full text Add to dashboard Cite

OBJECTIVE-Visceral obesity and elevated plasma free fatty acids are predisposing factors for type 2 diabetes. Chronic exposure to these lipids is detrimental for pancreatic ␤-cells, resulting in reduced insulin content, defective insulin secretion, and apoptosis. We investigated the involvement in this phenomenon of microRNAs (miRNAs), a class of noncoding RNAs regulating gene expression by sequence-specific inhibition of mRNA translation. RESEARCH DESIGN AND METHODS-We analyzed miRNA expression in insulin-secreting cell lines or pancreatic islets exposed to palmitate for 3 days and in islets from diabetic db/db mice. We studied the signaling pathways triggering the changes in miRNA expression and determined the impact of the miRNAs affected by palmitate on insulin secretion and apoptosis.RESULTS-Prolonged exposure of the ␤-cell line MIN6B1 and pancreatic islets to palmitate causes a time-and dose-dependent increase of miR34a and miR146. Elevated levels of these miRNAs are also observed in islets of diabetic db/db mice. miR34a rise is linked to activation of p53 and results in sensitization to apoptosis and impaired nutrient-induced secretion. The latter effect is associated with inhibition of the expression of vesicle-associated membrane protein 2, a key player in ␤-cell exocytosis. Higher miR146 levels do not affect the capacity to release insulin but contribute to increased apoptosis. Treatment with oligonucleotides that block miR34a or miR146 activity partially protects palmitate-treated cells from apoptosis but is insufficient to restore normal secretion. CONCLUSIONS-Our findings suggest that at least part of the detrimental effects of palmitate on ␤-cells is caused by alterations in the level of specific miRNAs. Diabetes 57:2728-2736, 2008

show abstract

Section: Diabetes Vol 57 October 2008mentioning

confidence: 60%

Alterations in MicroRNA Expression Contribute to Fatty Acid–Induced Pancreatic β-Cell Dysfunction

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Recent studies have indicated that activation of JNK, which is best known for its role in regulation of cell survival and apoptosis in response to different stimuli (25)(26)(27)(28), can cause ROS generation in some systems (42,43). For example, JNK activation has been linked to ROS production by tumor necrosis factor (TNF; ref.…”

Section: Resultsmentioning

confidence: 99%

c-Jun NH2-Terminal Kinase Signaling Axis Regulates Diallyl Trisulfide–Induced Generation of Reactive Oxygen Species and Cell Cycle Arrest in Human Prostate Cancer Cells

et al. 2006

View full text Add to dashboard Cite

We have shown previously that generation of reactive oxygen species (ROS) is a critical event in G 2 -M phase cell cycle arrest caused by diallyl trisulfide (DATS), which is a highly promising anticancer constituent of processed garlic. Using DU145 and PC-3 human prostate cancer cells as a model, we now report a novel mechanism involving c-Jun NH 2 -terminal kinase (JNK) signaling axis, which is known for its role in regulation of cell survival and apoptosis, in DATS-induced ROS production. The DATS-induced ROS generation, G 2 -M phase cell cycle arrest and degradation, and hyperphosphorylation of Cdc25C were significantly attenuated in the presence of EUK134, a combined mimetic of superoxide dismutase and catalase. Interestingly, the DATS-induced ROS generation and G 2 -M phase cell cycle arrest were also inhibited significantly in the presence of desferrioxamine, an iron chelator, but this protection was not observed with iron-saturated desferrioxamine. DATS treatment caused a marked increase in the level of labile iron that was accompanied by degradation of light chain of iron storage protein ferritin. Interestingly, DATSmediated degradation of ferritin, increase in labile iron pool, ROS generation, and/or cell cycle arrest were significantly attenuated by ectopic expression of a catalytically inactive mutant of JNK kinase 2 and RNA interference of stressactivated protein kinase/extracellular signal-regulated kinase 1 (SEK1), upstream kinases in JNK signal transduction pathway. In conclusion, the present study provides experimental evidence to indicate existence of a novel pathway involving JNK signaling axis in regulation of DATS-induced ROS generation.

show abstract

“…Accordingly, further up regulation of cellular ROS, such as shown here after treatment with PAC-1A can be used to selectively target cancer cells over normal cells (44). ROS production in NB cells is correlated with multitude of signal transduction such as the activation of the JNK/SAPK or other pro-apoptotic MAPK, loss of ∆Ψm and translocation or degradation of mitochondrial key proteins of the intrinsic apoptotic pathway (45). Accordingly, as shown here the PAC-1A induced loss of Bcl-2 and MCL-1, deactivation of PARP-1 and executor caspase-3 in SMS-KCNR NB cells could be partially inhibited by the block of excessive ROS generation via co-treatment with an anti-oxidant.…”

Section: Discussionmentioning

confidence: 99%

Purified cranberry proanthocyanidines (PAC-1A) cause pro-apoptotic signaling, ROS generation, cyclophosphamide retention and cytotoxicity in high-risk neuroblastoma cells

Vorsa

2011

Int J Oncol

View full text Add to dashboard Cite

Abstract. Optimized purification of oligomeric proanthocyanidines (PAC) from cranberry generated PAC-1A which selectively affected the viability of various neuroblastoma (NB) cell lines representing a spectrum of high-risk NB features. PAC-1A caused a loss of mitochondrial transmembrane depolarization potential (∆Ψm) and increased generation of reactive oxygen species (ROS) which was directly correlated to the modulation of apoptotic marker proteins in SMS-KCNR cells. PAC-1A reduced the expression of pro-survival (Bcl-2, MCL-1, Bcl-xL) and increased levels of pro-apoptotic (Bax, Bad, Bid) Bcl family proteins, upregulated the activity of SAPK/JNK MAPK and downregulated expression or activity of PI3K/AKT/mTOR pathway components. PAC-1A increased the cellular uptake/ retention of cyclophosphamide (CP). PAC-1A and CP synergistically increased cytotoxicity and expression of pro-apoptotic markers, reduced cellular glutathione (GSH) and superoxide dismutase (SOD) levels. Additional features of PAC-1A as an anticancer drug as shown in SMS-KCNR NB cells include delay of cell cycle progression and induction of cell death via TNF-family death receptor activity, thus, targeting both the extrinsic and intrinsic pathway of apoptosis. PAC-1A partially blocked the cell cycle in G2/M phase which correlated with a decrease of the G0/G1 subpopulation, upregulation of cyclin D1 and downregulation of CDK6 and p27 expression. In summary, PAC-1A has demonstrated chemotherapeutic potential to treat a broad spectrum of NBs including highly malignant tumors that show resistance to standard chemotherapeutics and apoptotic stimuli.

show abstract

Synergistic activation of JNK/SAPK induced by TNF-α and IFN-γ: Apoptosis of pancreatic β-cells via the p53 and ROS pathway

Cited by 99 publications

References 39 publications

Alterations in MicroRNA Expression Contribute to Fatty Acid–Induced Pancreatic β-Cell Dysfunction

Alterations in MicroRNA Expression Contribute to Fatty Acid–Induced Pancreatic β-Cell Dysfunction

c-Jun NH2-Terminal Kinase Signaling Axis Regulates Diallyl Trisulfide–Induced Generation of Reactive Oxygen Species and Cell Cycle Arrest in Human Prostate Cancer Cells

Purified cranberry proanthocyanidines (PAC-1A) cause pro-apoptotic signaling, ROS generation, cyclophosphamide retention and cytotoxicity in high-risk neuroblastoma cells

Contact Info

Product

Resources

About