Exendin-4 Protects Pancreatic Beta Cells from the Cytotoxic Effect of Rapamycin by Inhibiting JNK and p38 Phosphorylation

Kawasaki, Yosuke; Harashima, Shin‐ichi; Sasaki, Masahiro; Mukai, Eri; Nakamura, Yoshinari; Harada, Norio; Toyoda, Kyosuke; Hamasaki, Azumi; Yamane, Shunsuke; Yamada, Chieko; Yamada, Yoko; Seino, Yutaka; Inagaki, Nobuya

doi:10.1055/s-0030-1249035

Cited by 20 publications

(19 citation statements)

References 24 publications

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“…Reason for that is not clear; however, we cannot exclude that other ROS are behind the involvement of p38 MAPK and JNK kinases upon apoptosis. Recently, it was demonstrated that exendin-4 inhibits cytotoxic induced b-cell death via a decreased phosphorylation of both p38 MAPK and JNK, through PKA signaling pathways (Kawasaki et al 2010), which is in line with our observation.…”

Section: Discussionsupporting

confidence: 93%

Exendin-4 protects endothelial cells from lipoapoptosis by PKA, PI3K, eNOS, p38 MAPK, and JNK pathways

Erdogdu

Eriksson

et al. 2013

Journal of Molecular Endocrinology

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Experimental studies have indicated that endothelial cells play an important role in maintaining vascular homeostasis. We previously reported that human coronary artery endothelial cells (HCAECs) express the glucagon-like peptide 1 (GLP1) receptor and that the stable GLP1 mimetic exendin-4 is able to activate the receptor, leading to increased cell proliferation. Here, we have studied the effect of exendin-4 and native GLP1 (7-36) on lipoapoptosis and its underlying mechanisms in HCAECs. Apoptosis was assessed by DNA fragmentation and caspase-3 activation, after incubating cells with palmitate. Nitric oxide (NO) and reactive oxidative species (ROS) were analyzed. GLP1 receptor activation, PKA-, PI3K/Akt-, eNOS-, p38 MAPK-, and JNK-dependent pathways, and genetic silencing of transfection of eNOS were also studied. Palmitate-induced apoptosis stimulated cells to release NO and ROS, concomitant with upregulation of eNOS, which required activation of p38 MAPK and JNK. Exendin-4 restored the imbalance between NO and ROS production in which ROS production decreased and NO production was further augmented. Incubation with exendin-4 and GLP1 (7-36) protected HCAECs against lipoapoptosis, an effect that was blocked by PKA, PI3K/Akt, eNOS, p38 MAPK, and JNK inhibitors. Genetic silencing of eNOS also abolished the anti-apoptotic effect afforded by exendin-4. Our results support the notion that GLP1 receptor agonists restore eNOS-induced ROS production due to lipotoxicity and that such agonists protect against lipoapoptosis through PKA-PI3K/Akt-eNOS-p38 MAPK-JNK-dependent pathways via a GLP1 receptor-dependent mechanism.

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Section: Discussionsupporting

confidence: 93%

Exendin-4 protects endothelial cells from lipoapoptosis by PKA, PI3K, eNOS, p38 MAPK, and JNK pathways

Erdogdu

Eriksson

et al. 2013

Journal of Molecular Endocrinology

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“…Consistent with this finding, it has been reported that rapamycin activates JNK in a human glioblastoma cell line that expresses a constitutively active mutant of the epidermal growth factor receptor [24]. Furthermore, rapamycin also increased JNK phosphorylation in MIN6 cells and Wistar rat pancreatic ilets [25]. Finally rapamycin was also shown to induce a transient activation of JNK in cells expressing wild-type p53 and a sustained activation in cells expressing mutant p53 [26].…”

Section: Discussionsupporting

confidence: 69%

Targeting the JNK Signaling Pathway Potentiates the Antiproliferative Efficacy of Rapamycin in LS174T Colon Cancer Cells

Benoit

Dormond-Meuwly

Demartines

et al. 2011

Journal of Surgical Research

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“…GLP-1 receptor agonists can inhibit the proapoptotic pathways triggered by a variety of stimuli, including IL-1β, TNF-α and rapamycin, by interfering with JNK and possibly p38 MAPK activation [15,19,46]. The cAMP/PKA/CREB cascade represents a central mechanism of GLP-1 action, specifically when this relates to promotion of beta cell survival [47], even though other signalling mediators may also be implicated [48,49].…”

Section: Discussionmentioning

confidence: 99%

Exendin-4 protects pancreatic beta cells from palmitate-induced apoptosis by interfering with GPR40 and the MKK4/7 stress kinase signalling pathway

et al. 2013

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Aims/hypothesis The mechanisms of the protective effects of exendin-4 on NEFA-induced beta cell apoptosis were investigated. Methods The effects of exendin-4 and palmitate were evaluated in human and murine islets, rat insulin-secreting INS-1E cells and murine glucagon-secreting alpha-TC1-6 cells. mRNA and protein expression/phosphorylation were measured by real-time RT-PCR and immunoblotting or immunofluorescence, respectively. Small interfering (si)RNAs for Ib1 and Gpr40 were used. Cell apoptosis was quantified by two independent assays. Insulin release was assessed with an insulin ELISA. Results Exposure of human and murine primary islets and INS-1E cells, but not alpha-TC1-6 cells, to exendin-4 inhibited phosphorylation of the stress kinases, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), and prevented apoptosis in response to palmitate. Exendin-4 increased the protein content of islet-brain 1 (IB1), an endogenous JNK blocker; however, siRNA-mediated reduction of IB1 did not impair the ability of exendin-4 to inhibit JNK and prevent apoptosis. Exendin-4 reduced G-protein-coupled receptor 40 (GPR40) expression and inhibited palmitateinduced phosphorylation of mitogen-activated kinase kinase (MKK)4 and MKK7. The effects of exendin-4 were abrogated in the presence of the protein kinase A (PKA) inhibitors, H89 and KT5720. Knockdown of GPR40, as well as use of a specific GPR40 antagonist, resulted in diminished palmitateinduced JNK and p38 MAPK phosphorylation and apoptosis. Furthermore, inhibition of JNK and p38 MAPK activity prevented palmitate-induced apoptosis. Conclusions/interpretation Exendin-4 counteracts the proapoptotic effects of palmitate in beta cells by reducing GPR40 expression and inhibiting MKK7-and MKK4-dependent phosphorylation of the stress kinases, JNK and p38 MAPK, in a PKA-dependent manner.

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Exendin-4 Protects Pancreatic Beta Cells from the Cytotoxic Effect of Rapamycin by Inhibiting JNK and p38 Phosphorylation

Cited by 20 publications

References 24 publications

Exendin-4 protects endothelial cells from lipoapoptosis by PKA, PI3K, eNOS, p38 MAPK, and JNK pathways

Exendin-4 protects endothelial cells from lipoapoptosis by PKA, PI3K, eNOS, p38 MAPK, and JNK pathways

Targeting the JNK Signaling Pathway Potentiates the Antiproliferative Efficacy of Rapamycin in LS174T Colon Cancer Cells

Exendin-4 protects pancreatic beta cells from palmitate-induced apoptosis by interfering with GPR40 and the MKK4/7 stress kinase signalling pathway

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