Enhanced airway smooth muscle cell thromboxane receptor signaling via activation of JNK MAPK and extracellular calcium influx

Lei, Ying; Cao, Yunxia; Zhang, Yaping; Edvinsson, Lars; Xu, Cang‐Bao

doi:10.1016/j.ejphar.2010.10.038

Cited by 17 publications

(18 citation statements)

References 55 publications

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“…We next observed that U46619 activated JNK and p38 MAPK by phosphorylation, which was almost completely blocked by pretreatment with SP600125 and SB203580. In line with our data, Bolla et al (15) found that activation of p38 MAPK in arteries treated with U46619 exists, and Lei et al (16) showed that U46619 promotes JNK phosphorylation in the bronchial smooth muscle. In addition, we also found that treatments of MM cells with SP600125 and SB203580 depressed U46619-induced protein expression of cyclin B1 and CDK1.…”

Section: Discussionsupporting

confidence: 92%

“…Baek et al (14) have reported that cinobufagin exhibits potent anticancer effects in MM, possibly through the reactive oxygen species-mediated activation of ERK, JNK, and p38 MAPK and subsequent activation of caspase 3 in U-266 cells. Moreover, TxA 2 /TP activation has been shown to participate in some physiological processes by activating JNK, p38 MAPK, and ERK1/2 (15)(16)(17). However, any association between COX/ TxA 2 /TP and MAPK signaling in MM cell proliferation is still elusive.…”

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confidence: 99%

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Thromboxane A2 Receptor Inhibition Suppresses Multiple Myeloma Cell Proliferation by Inducing p38/c-Jun N-terminal Kinase (JNK) Mitogen-activated Protein Kinase (MAPK)-mediated G2/M Progression Delay and Cell Apoptosis

Liu

Tao

Liu

et al. 2016

Journal of Biological Chemistry

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Multiple myeloma (MM) is a plasma cell malignancy without effective therapeutics. Thromboxane A 2 (TxA 2 )/TxA 2 receptor (T prostanoid receptor (TP)) modulates the progression of some carcinomas; however, its effects on MM cell proliferation remain unclear. In this study, we evaluated cyclooxygenase (COX) enzymes and downstream prostaglandin profiles in human myeloma cell lines RPMI-8226 and U-266 and analyzed the effects of COX-1/-2 inhibitors SC-560 and NS-398 on MM cell proliferation. Our observations implicate COX-2 as being involved in modulating cell proliferation. We further incubated MM cells with prostaglandin receptor antagonists or agonists and found that only the TP antagonist, SQ29548, suppressed MM cell proliferation. TP silencing and the TP agonist, U46619, further confirmed this finding. Moreover, SQ29548 and TP silencing promoted MM cell G 2 /M phase delay accompanied by reducing cyclin B1/cyclin-dependent kinase-1 (CDK1) mRNA and protein expression. Notably, cyclin B1 overexpression rescued MM cells from G 2 /M arrest. We also found that the TP agonist activated JNK and p38 MAPK phosphorylation, and inhibitors of JNK and p38 MAPK depressed U46619-induced proliferation and cyclin B1/CDK1 protein expression. In addition, SQ29548 and TP silencing led to the MM cell apoptotic rate increasing with improving caspase 3 activity. The knockdown of caspase 3 reversed the apoptotic rate. Taken together, our results suggest that TxA 2 /TP promotes MM cell proliferation by reducing cell delay at G 2 /M phase via elevating p38 MAPK/JNK-mediated cyclin B1/CDK1 expression and hindering cell apoptosis. The TP inhibitor has potential as a novel agent to target kinase cascades for MM therapy. Multiple myeloma (MM)3 is a B-cell malignancy characterized by the clonal proliferation of neoplastic plasma cells in the bone marrow (BM). It accounts for 12% of all malignant hematological neoplasms and is the second most frequent hematological malignancy (1). Recently, despite the improved therapeutic effect of newly approved chemotherapeutics, including thalidomide, lenalidomide, and bortezomib, and stem cell transplantation, MM remains incurable, with only a marginal increase in the 5-year relative survival rate and a high incidence of relapse (2, 3). Thus, identification of novel therapeutic targets for MM is urgently needed.Growing evidence demonstrates that thromboxane A 2 (TxA 2 )-related molecules are actively involved in tumor progression (4, 5). TxA 2 is one of the five primary prostaglandins (PGs) generated from arachidonic acid (AA) through the cyclooxygenases (COX-1 and COX-2) and TxA 2 synthase pathways and exerts its biological activities through the TxA 2 receptor (T prostanoid receptor (TP)) located on the cell surface. TP belongs to the G-protein-coupled receptor superfamily and is expressed as two isoforms in humans, named TP ␣ and TP ␤ (6). Notably, TxA 2 stimulates proliferation of several types of cells, including oligodendrocytes (7), smooth muscle cells (8), and lung cancer cells (9). For example, ...

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Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 99%

Thromboxane A2 Receptor Inhibition Suppresses Multiple Myeloma Cell Proliferation by Inducing p38/c-Jun N-terminal Kinase (JNK) Mitogen-activated Protein Kinase (MAPK)-mediated G2/M Progression Delay and Cell Apoptosis

Liu

Tao

Liu

et al. 2016

Journal of Biological Chemistry

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“…The protein of cerebral vessels was extracted as described before [37]. After gel eletrophoresis and protein transfer, membrane was then blocked in 5% non-fat milk.…”

Section: Methodsmentioning

confidence: 99%

Secondhand smoke exposure induces Raf/ERK/MAPK-mediated upregulation of cerebrovascular endothelin ETA receptors

Cao

Zhang

et al. 2011

BMC Neurosci

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BackgroundCigarette smoking enhances the risk of stroke. However, the underlying molecular mechanisms are largely unknown. The present study established an in vivo rat secondhand cigarette smoking (SHS) model and examined the hypothesis that SHS upregulates endothelin receptors with increased cerebrovascular contraction via the Raf/extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinases (MAPK) pathway.ResultsRats were exposed to SHS for up to 8 weeks. The cerebral artery vasoconstriction was recorded by a sensitive myograph. The mRNA and protein expressions for endothelin receptors in cerebral arteries were studied by real-time PCR and Western blot. Compared to fresh air exposed rats, cerebral arteries from SHS rats exhibited stronger contractile responses (P < 0.05) mediated by endothelin type A (ETA) receptors. The expressions of mRNA and protein for ETA receptors in the cerebral arteries from SHS rats were higher (P < 0.05) than that in control. SHS did not affect endothelin type B (ETB) receptor-mediated contractions, mRNA or protein levels. The results suggest that SHS upregulates ETA, but not ETB receptors in vivo. After SHS exposure, the mRNA levels of Raf-1 and ERK1/2, the protein expression of phosphorylated (p)-Raf-1 and p-ERK1/2 were increased (P < 0.05). Raf-1 inhibitor, GW5074 suppressed the enhanced ETA receptor-mediated contraction, mRNA and protein levels induced by SHS. In addition, GW5074 inhibited the SHS-caused increased mRNA and phosphorylated protein levels of Raf-1 and ERK1/2, suggesting that SHS induces activation of the Raf/ERK/MAPK pathway.ConclusionsSHS upregulates cerebrovascular ETA receptors via the Raf/ERK/MAPK pathway, which provides novel understanding of mechanisms involved in SHS-associated stroke.

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“…The chemical inhibitors of JNK family members are less selective than MEK (then ERK1/2) and p38 MAPK inhibitors and therefore somewhat less useful for definitive studies of kinase action in cells. However, recent evidences support an important role for JNK in regulation of airway smooth muscle contraction (Lei et al, 2011). SP600125, a JNK inhibitor, attenuates vascular smooth muscle contraction and human prostate smooth muscle induced by norepinephrine and phenylephrine (Lee et al, 2006;Strittmatter et al, 2012).…”

Section: Jnk Pathwaymentioning

confidence: 99%

MAP Kinase-Mediated and MLCK-Independent Phosphorylation of MLC20 in Smooth Muscle Cells

Deng¹,

Deng²,

Xue³

2012

Current Basic and Pathological Approaches to the Function of Muscle Cells and Tissues - From Molecules to Humans

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Enhanced airway smooth muscle cell thromboxane receptor signaling via activation of JNK MAPK and extracellular calcium influx

Cited by 17 publications

References 55 publications

Thromboxane A2 Receptor Inhibition Suppresses Multiple Myeloma Cell Proliferation by Inducing p38/c-Jun N-terminal Kinase (JNK) Mitogen-activated Protein Kinase (MAPK)-mediated G2/M Progression Delay and Cell Apoptosis

Thromboxane A2 Receptor Inhibition Suppresses Multiple Myeloma Cell Proliferation by Inducing p38/c-Jun N-terminal Kinase (JNK) Mitogen-activated Protein Kinase (MAPK)-mediated G2/M Progression Delay and Cell Apoptosis

Secondhand smoke exposure induces Raf/ERK/MAPK-mediated upregulation of cerebrovascular endothelin ETA receptors

MAP Kinase-Mediated and MLCK-Independent Phosphorylation of MLC20 in Smooth Muscle Cells

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