Activation of PI3K-Akt pathway mediates antiapoptotic effects of β-adrenergic agonist in airway eosinophils

Machida, Kentaro; Inoue, Hiromasa; Matsumoto, Koichiro; Tsuda, Miyuki; Fukuyama, Satoru; Kojima, Hiroshi; Aizawa, Hisamichi; Kureishi, Yasuko; Hara, Nobuyuki; Nakanishi, Yoichi

doi:10.1152/ajplung.00131.2004

Cited by 40 publications

(32 citation statements)

References 58 publications

(71 reference statements)

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“…Agonist binding to the β-AR receptor can transactivate EGFR leading to phosphorylation of Akt and ERK1/2, which are known to promote tumor progression [11,12] . Coincidently, HIF-1α expression and activity are regulated by major signal transduction pathways including PI3K/Akt/mTOR and Ras/ Raf/ERK1/2 [7] .…”

Section: Introductionmentioning

confidence: 99%

HIF-1α links β-adrenoceptor agonists and pancreatic cancer cells under normoxic condition

Qing

Zhang

et al. 2009

Acta Pharmacol Sin

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Aim: To examine whether β-adrenoceptor (β-AR) agonists can induce hypoxia-inducible factor (HIF)-1α accumulation which then upregulate the expression of its target genes in pancreatic cancer cells at normoxia, and to further elucidate the mechanism involved. Methods: Pulse-chase assay, RT-PCR, and Western blot were employed to detect the effects of β-AR agonists and antagonists, siRNA as well as several inhibitors of signal transduction pathways on MIA PaCa2 and BxPC-3 pancreatic cancer cells. Results: Treatment of pancreatic cancer cell lines with β-AR agonists led to accumulation of HIF-1α and then up-regulated expression of its target genes independently of oxygen levels. The induction was partly or completely inhibited not only by β-AR antagonists but also by inhibitors of PKA transduction pathways and by siHIF-1α. Both β1-AR and β2-AR agonists produced the above-mentioned effects, but β2-AR agonist was more potent. Conclusion: Activation of β-AR receptor transactivates epidermal growth factor receptor (EGFR) and then elicites Akt and ERK1/2 in a PKA-dependent manner, which together up-regulate levels of HIF-1α and downstream target genes independently of oxygen level. Our data suggest a novel mechanism in pancreatic cancer cells that links β-AR and HIF-1α signaling under normoxic conditions, with implications for the control of glucose transport, angiogenesis and metastasis.

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Section: Introductionmentioning

confidence: 99%

HIF-1α links β-adrenoceptor agonists and pancreatic cancer cells under normoxic condition

Qing

Zhang

et al. 2009

Acta Pharmacol Sin

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“…One possible mechanism contributing to this detrimental activity could be the prevention of eosinophil clearance by inhibition of apoptosis resulting in more severe inflammatory response and asthma symptoms. In line with this, clinically used β 2 -agonists, such as salbutamol, fenoterol, formoterol and salmeterol, have been reported to increase human eosinophil longevity via inhibition of apoptosis [7,12]. However, the mechanism by which β 2 agonists prolong eosinophil survival remains largely unknown.…”

Section: Introductionmentioning

confidence: 91%

“…13 such as forskolin and prostaglandin E 2 as well as cAMP analogue dibutyryl-cAMP have been show to prolong eosinophil survival [12][13][14][15][16].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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Salbutamol delays human eosinophil apoptosis via a cAMP-dependent mechanism

Kankaanranta¹,

Parkkonen²,

Ilmarinen³

et al. 2011

Pulmonary Pharmacology & Therapeutics

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Eosinophils play a major role in asthma. One described mechanism leading to the impaired clearance of these cells from the lung is the delay in their programmed cell death (apoptosis). β 2 -adrenoceptor agonists have been shown to prolong survival and delay apoptosis of eosinophils. The aim of the present study was to evaluate the mechanisms, especially the role of cAMP pathway, in the prolongation of human eosinophil survival by a selective β 2 -agonist salbutamol.Isolated human peripheral blood eosinophils were cultured in the absence or presence of a β 2 -agonist salbutamol and the indicated antagonists/inhibitors under sterile conditions. Apoptosis was measured by using the relative DNA fragmentation assay and Annexin-V binding.Salbutamol prolonged survival of human eosinophils and it was inhibited by a β-receptor antagonist propranolol and mimicked by cell-permeant cAMP analogues dibutyryl-and 8-bromo-cAMP. Pharmacological inhibitors of adenylyl cyclase (SQ-22,536) and protein kinase A (Rp-8-CPT-cAMPS) antagonized the effects of salbutamol. The survival-prolonging action of salbutamol was potentiated by a phosphodiesterase inhibitor rolipram (EC 50 for the salbutamol effect was 13.6 ± 4.0 and 8.1 ± 3.1 nM in the absence and presence of rolipram, respectively; P=0.0142, n=10).In contrast, inhibition of Ca 2+ -activated K + -channels by apamin, charybdotoxin, iberiotoxin or paxilline did not affect the ability of salbutamol to prolong eosinophil survival.Taken together, the present results suggest that salbutamol at clinically relevant concentrations decreases apoptosis in human eosinophils by activating the cannonical β 2 -receptor-adenylyl cyclase-cAMP-protein kinase A pathway.

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“…Although most well-described β-adrenergic signalling involves cyclic AMP, atypical signalling also occurs, in which the G-protein βγ subunits may initiate crosstalk with other signalling pathways in addition to cyclic AMP [12]. An example of this is the way G-proteincoupled receptors can use PI3K for signalling, possibly by βγ subunits released after G-protein activation [13]; moreover, some β 2 -adrenoceptor responses have been shown to be mediated via PI3K [14,15].…”

Section: Introductionmentioning

confidence: 99%

β2-Adrenergic activation increases glycogen synthesis in L6 skeletal muscle cells through a signalling pathway independent of cyclic AMP

2006

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Aims/hypothesis In skeletal muscle, the storage of glycogen by insulin is regulated by glycogen synthase, which is regulated by glycogen synthase kinase 3 (GSK3). Here we examined whether adrenergic receptor activation, which can increase glucose uptake, regulates glycogen synthesis in L6 skeletal muscle cells. Methods We used L6 cells and measured glycogen synthesis (as incorporation of D-[U-14 C]glucose into glycogen) and GSK3 phosphorylation following adrenergic activation. Results Insulin (negative logarithm of median effective concentration [pEC 50 ] 8.2± 0.3) and the β-adrenergic agonist isoprenaline (pEC 50 7.5±0.3) induced a twofold increase in glycogen synthesis in a concentration-dependent manner. The α 1 -adrenergic agonist cirazoline and α 2 -adrenergic agonist clonidine had no effect. Both insulin and isoprenaline phosphorylated GSK3. The β-adrenergic effect on glycogen synthesis is mediated by β 2 -adrenoceptors and not β 1 -/β 3 -adrenoceptors, and was not mimicked by 8-bromo-cyclic AMP or cholera toxin, and also was insensitive to pertussis toxin, indicating no involvement of cyclic AMP or inhibitory G-protein (G i ) signalling in the β 2 -adrenergic effect on glycogen synthesis. 12-O-tetradecanoylphorbol-13-acetate (TPA) increased glycogen synthesis 2.5-fold and phosphorylated GSK3 fourfold.Inhibition of protein kinase C (PKC) isoforms with 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrollo(3,4-c)-carbazole (Gö6976; inhibits conventional and novel PKCs) or 2-[1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl]-3-(1H-indol-3-yl)maleimide (Gö6983; inhibits conventional, novel and atypical PKCs) inhibited the stimulatory TPA effect, but did not significantly inhibit glycogen synthesis mediated by insulin or isoprenaline. Inhibition of phosphatidylinositol 3-kinase (PI3K) with wortmannin inhibited the effects of insulin and isoprenaline on glycogen synthesis. Conclusions/interpretation These results demonstrate that in L6 skeletal muscle cells adrenergic stimulation through β 2 -adrenoceptors, but not involving cyclic AMP or G i , activates a PI3K pathway that stimulates glycogen synthesis through GSK3.

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Activation of PI3K-Akt pathway mediates antiapoptotic effects of β-adrenergic agonist in airway eosinophils

Cited by 40 publications

References 58 publications

HIF-1α links β-adrenoceptor agonists and pancreatic cancer cells under normoxic condition

HIF-1α links β-adrenoceptor agonists and pancreatic cancer cells under normoxic condition

Salbutamol delays human eosinophil apoptosis via a cAMP-dependent mechanism

β2-Adrenergic activation increases glycogen synthesis in L6 skeletal muscle cells through a signalling pathway independent of cyclic AMP

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