Hypertonic environment elicits cyclooxygenase-2-driven prostaglandin E2 generation by colon cancer cells: Role of cytosolic phospholipase A2-α and kinase signaling pathways

Gentile, Luciana Boffoni; Piva, Bruno; Capizzani, Bianca C.; Furlaneto, Luiz G.B.; Moreira, Luciana Sarmento; Zamith-Miranda, Daniel; Diaz, Bruno L.

doi:10.1016/j.plefa.2009.11.005

Cited by 11 publications

(13 citation statements)

References 53 publications

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“…Here, we provide proof of principle that AVX002 potently inhibits cPLA2α as we for the first time demonstrate that AVX002 is an inhibitor of cPLA2α enzyme activity in synoviocytes (Figure 2D). Analogous effects of cPLA2α inhibition of enzyme activity, cytokine-induced AA release, PGE2 production and gene expression has previously been demonstrated with three other chemical inhibitors resembling AVX002 and ATK in chemical structure; MAFP, and the trifluoromethyl ketone analogue of EPA (EPACOCF3) [38–41]. Based on these results and the herein reported observations on the effects of AVX002 and ATK in our model system, we postulate that the observed effects of AVX002 are due to inhibition of cPLA2α enzyme activity.…”

Section: Discussionmentioning

confidence: 96%

Cytosolic Phospholipase A2 Regulates TNF-Induced Production of Joint Destructive Effectors in Synoviocytes

et al. 2013

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IntroductionRheumatoid arthritis (RA) is an inflammatory disease of the joint characterized by chronic synovitis causing pain, swelling and loss of function due to destruction of cartilage and bone. The complex series of pathological events occurring in RA is largely regulated via excessive production of pro-inflammatory cytokines, the most prominent being tumor necrosis factor (TNF). The objective of this work was to elucidate possible involvement of group IVA cytosolic phospholipase A2 (cPLA2α) in TNF-induced regulation of synovitis and joint destructive effectors in RA, to evaluate the potential of cPLA2α as a future therapeutic target.MethodsThe involvement of cPLA2α in tumor necrosis factor (TNF)-induced intracellular signaling cascades in synoviocytes (synovial fibroblast-like cells) was analyzed by arachidonic acid (AA) release assay, synoviocyte enzyme activity assay, gene expression analysis by real-time PCR and ELISA immunoassay for the detection of prostaglandin E2 (PGE2), interleukin 8 (IL8) and stromelysin-1 (MMP3), respectively. ResultsInhibitors of cPLA2α enzyme activity (AVX002, ATK) significantly reduced TNF-induced cellular release of AA, PGE2, IL8 and MMP3. This reduction was evident both at transcriptional, protein or metabolite levels. Interestingly, cPLA2α inhibition affected several key points of the arachidonyl cascade; AA-release, cyclooxygenase-2 (COX2) expression and PGE2 production. Furthermore, the results suggest that cPLA2α is subject to transcriptional auto-regulation as inhibition of cPLA2α resulted in reduced PLA2G4A gene expression in TNF-stimulated synoviocytes. ConclusionscPLA2α appears to be an important regulator of central effectors of inflammation and joint destruction, namely MMP3, IL8, COX2, and PGE2. Decreased transcription of the PLA2G4A and COX2 genes in response to cPLA2α enzyme inhibition further suggest a self-reinforcing effect of cPLA2α inhibition in response to TNF. Collectively, these results support that cPLA2α is an attractive therapeutic target candidate as its inhibition reduces the production of multiple key pro-inflammatory factors involved in RA pathogenesis.

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Section: Discussionmentioning

confidence: 96%

Cytosolic Phospholipase A2 Regulates TNF-Induced Production of Joint Destructive Effectors in Synoviocytes

et al. 2013

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“…41) Mitogen-activated kinases (MAPKs) including ERK, JNK and p38 MAPK induce transcriptional activation of MMP genes. 42,43) Another important transcriptional regulator of MMPs is NF-kB. Pyrrolidine dithiocarbamate (PDTC), an NF-kB inhibitor, up-regulated MMP-1 and MMP-13 in IL-1b-stimulated synoviocytes, suggesting the importance of NF-kB in PDTC-induced anti-inflammatory regulation via inhibition of MMP-1 and -13.…”

Section: Discussionmentioning

confidence: 99%

Emodin Inhibits Proinflammatory Responses and Inactivates Histone Deacetylase 1 in Hypoxic Rheumatoid Synoviocytes

Song

Jeong

et al. 2011

Biological & Pharmaceutical Bulletin

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“…21, 22, 23, 24 Many studies have shown that cPLA2 α is synchronously overexpressed and participates in tumorigenesis through producing sufficient substrates for the metabolic cascade of COX2/PGE2 and other pathways. 25, 26, 27, 28 However, the functions of cPLA2 α in breast cancer migration and invasion remain to be elucidated.…”

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confidence: 99%

cPLA2α mediates TGF-β-induced epithelial–mesenchymal transition in breast cancer through PI3k/Akt signaling

Chen

Luo

et al. 2017

Cell Death Dis

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A high incidence of tumor recurrence and metastasis has been reported in breast cancer patients; nevertheless, the underlying molecular mechanisms are largely unknown. Epithelial–mesenchymal transition (EMT), which is induced by transforming growth factor-β (TGF-β), has been implicated in tumorigenesis and breast cancer metastasis. EMT events are now directly associated with tumor metastasis, and this progress is dependent on the inflammatory microenvironment. Cytosolic phospholipase A2α (cPLA2α) has been shown to participate in a series of biological processes including inflammation and cancer development. However, the role and molecular mechanism of cPLA2α in breast cancer EMT and metastasis remain enigmatic. In this study, we found that cPLA2α was commonly overexpressed in most human breast cancer tissues and significantly correlated with a poor prognosis for human breast cancer. Functional studies demonstrated that cPLA2α overexpression was significantly associated with elevated migration and invasion in MDA-MB-231 and T47D cells. Conversely, reduced cPLA2α expression strongly attenuated metastasis and the EMT program of MDA-MB-231 cells. Further study found that knockdown of cPLA2α in MDA-MB-231 cells inhibited TGF-β-induced EMT through the PI3K/Akt signaling pathway. Animal experiments revealed that cPLA2α downregulation in MDA-MB-231 cells markedly restrained tumorigenesis and metastasis in vivo. This study indicates the potential role of cPLA2α in breast cancer metastasis and indicates that this molecule is a promising therapeutic target for breast cancer.

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Hypertonic environment elicits cyclooxygenase-2-driven prostaglandin E2 generation by colon cancer cells: Role of cytosolic phospholipase A2-α and kinase signaling pathways

Cited by 11 publications

References 53 publications

Cytosolic Phospholipase A2 Regulates TNF-Induced Production of Joint Destructive Effectors in Synoviocytes

Cytosolic Phospholipase A2 Regulates TNF-Induced Production of Joint Destructive Effectors in Synoviocytes

Emodin Inhibits Proinflammatory Responses and Inactivates Histone Deacetylase 1 in Hypoxic Rheumatoid Synoviocytes

cPLA2α mediates TGF-β-induced epithelial–mesenchymal transition in breast cancer through PI3k/Akt signaling

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