Sulindac independently modulates extracellular signal–regulated kinase 1/2 and cyclic GMP–dependent protein kinase signaling pathways

Rice, Pamela L.; Peters, Stevany L.; Beard, Keith; Ahnen, Dennis J.

doi:10.1158/1535-7163.mct-05-0210

Cited by 20 publications

(17 citation statements)

References 17 publications

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“…The kinetics of CCK's anorectic action are similar to that of amylin (51,59); however, because the target site in the present study was the AP and not the NTS, as in the studies by Sutton and colleagues (58,59), the uptake of U0126 and duration of inhibitor activity may differ between the two brain areas. Furthermore, cell culture studies have shown that U0126 effectively blocked ERK1/2 phosphorylation as early as after 30 min of incubation with U0126 in colon cancer cells (48). In parallel, the effect of amylin dosage was also assessed.…”

Section: Discussionmentioning

confidence: 99%

Involvement of the extracellular signal-regulated kinase 1/2 signaling pathway in amylin's eating inhibitory effect

Potes

Boyle

Wookey

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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Potes CS, Boyle CN, Wookey PJ, Riediger T, Lutz TA. Involvement of the extracellular signal-regulated kinase 1/2 signaling pathway in amylin's eating inhibitory effect. Am J Physiol Regul Integr Comp Physiol 302: R340 -R351, 2012. First published November 30, 2011 doi:10.1152/ajpregu.00380.2011.-Peripheral amylin inhibits eating via the area postrema (AP). Because amylin activates the extracellular-signal regulated kinase 1/2 (ERK) pathway in some tissues, and because ERK1/2 phosphorylation (pERK) leads to acute neuronal responses, we postulated that it may be involved in amylin's eating inhibitory effect. Amylin-induced ERK phosphorylation (pERK) was investigated by immunohistochemistry in brain sections containing the AP. pERK-positive AP neurons were double-stained for the calcitonin 1a/b receptor, which is part of the functional amylin-receptor. AP sections were also phenotyped using dopamine-␤-hydroxylase (DBH) as a marker of noradrenergic neurons. The effect of fourth ventricular administration of the ERK cascade blocker U0126 on amylin's eating inhibitory action was tested in feeding trials. The number of pERK-positive neurons in the AP was highest ϳ10 -15 min after amylin treatment; the effect appeared to be dosedependent (5-20 g/kg amylin). A portion of pERK-positive neurons in the AP carried the amylin-receptor and 22% of the pERK-positive neurons were noradrenergic. Pretreatment of rats with U0126 decreased the number of pERK-positive neurons in the AP after amylin injection. U0126 also attenuated the ability of amylin to reduce eating, at least when the animals had been fasted 24 h prior to the feeding trial. Overall, our results suggest that amylin directly stimulates pERK in AP neurons in a time-and dose-dependent manner. Part of the AP neurons displaying pERK were noradrenergic. At least under fasting conditions, pERK was shown to be a necessary part in the signaling cascade mediating amylin's anorectic effect.ERK; MAPK; area postrema; amylin receptor; U0126 THE HOMEOSTATIC SYSTEM CONTROLLING food intake and body weight relies to a large extent on peripheral satiation signals.One of these signals is amylin, a peptide cosecreted with insulin by pancreatic ␤-cells in response to nutrient ingestion (12, 41). At near-physiological plasma concentrations, amylin effectively decreases food intake in rats, and is considered a physiological satiation signal (4, 27). The amylin analog pramlintide causes weight loss in obese humans that is accompanied by sustained reductions in 24-h food intake, portion sizes, fast food intake, and binge eating tendencies (5, 57).Pharmacological and lesioning studies implicate the area postrema (AP) as the primary site of amylin's anorectic action (29,30,35), and an excitatory action of amylin on AP neurons has been confirmed by electrophysiological studies (49). Immunohistochemical studies using the immediate early gene product c-Fos as a marker of neuronal activation showed that peripheral amylin activates the AP, and subsequently the nucleus of the solitary tract (NTS),...

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Section: Discussionmentioning

confidence: 99%

Involvement of the extracellular signal-regulated kinase 1/2 signaling pathway in amylin's eating inhibitory effect

Potes

Boyle

Wookey

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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“…NSAIDS are well studied class of chemopreventive agents and have been shown to act through both COX dependent 19,20 and independent pathways. 21,22 Rofecoxib and celeocoxib were introduced into the market as selective COX-2 inhibitors with nongastrointestinal side effects, but their prolonged use has raised concern about their adverse cardiovascular effects. 23 Since the use of these agents for cancer therapy has not been fully evaluated, understanding the underlying mechanisms of these agents can lead to further development of novel therapeutic agents for PC utilizing the nonsteroidal scaffolds such as COX-2 inhibitors.…”

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confidence: 99%

A novel copper complex of 3‐benzoyl‐α methyl benzene acetic acid with antitumor activity mediated via cyclooxygenase pathway

Ahmed

Adsule

Ali

et al. 2006

Intl Journal of Cancer

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Pancreatic cancer (PC) is characterized as one of the deadliest malignancies and its treatment is a great challenge to clinical oncologists. Expression of COX-2 is detectable in 75% of PCs among which 50% showed overexpression, suggesting the importance of COX-2 enzyme and its metabolic product prostaglandin E2 (PGE 2 ) in PC. Here the authors report the synthesis and biological activity of a novel COX-2 inhibitor, FPA-306, and its effects on PC cells with different levels of COX-2 expression. Using MTT assay, the authors found a significant growth inhibition of BxPC-3 cells treated by FPA-306 with an IC 50 of 10 lmol/ L, which was lower than that of ketoprofen (IC 50 5 35.4 lmol/L) and celecoxib (IC 50 > 100 lmol/L). There was no such effect found in MIAPaCa cell line, which does not express COX-2. The authors also found dose dependent reduction in cell survival and induction of apoptosis by FPA-306 treatment in BxPC-3 cells but not in MIAPaCa cells. These results were correlated with apoptosis data and secreted PGE 2 levels. The molecular modeling of FPA-306 in the COX-2 active site showed that FPA-306 is potentially able to inhibit the activity of enzyme by blocking the active site, thereby resulting in decreased PGE 2 production. The authors also found a significant reduction of COX-2 at the mRNA and protein levels together with downregulation of NF-jB DNA binding activity and its downstream genes, Bcl-2 and survivin. These results suggest that FPA-306 is an effective and potent agent in inhibiting the growth of PC cells. ' 2006 Wiley-Liss, Inc.Key words: pancreatic cancer cells; cyclooxygenase-2; NSAIDS; prostaglandin E 2 Pancreatic cancer (PC) is the fourth leading cause of cancer related death in the United States. An estimated 33,730 individuals will be diagnosed with PC in the year of 2006, with an almost similar incidence rate among males and females. 1 PC is relatively resistant to all currently available therapeutic approaches including radiotherapy and chemotherapy. Palliative care is the only option because most of the patients are also not suitable for surgery at the time of diagnosis. Thus, delayed diagnosis partly due to indolent nature of pancreatic tumor progression and lack of effective therapy results in limited survival.From a mechanistic point of view, several molecular pathways have been identified such as Ras-Raf-MEK-ERK, PI3K/Akt and NF-jB pathway that are believed to be important in the development, progression and metastasis of PC. In addition, the involvement of cyclooxygenase (COX) and lipoxygenase family of enzymes in the development and progression of PC has been appreciated recently. 2 The COX family of enzymes catalyzes the ratelimiting step in conversion of arachidonic acid into prostaglandins. 3 Three isoforms of COX enzyme have been reported-COX-1, COX-2 and COX-3. 4 COX-1 is constitutively expressed in many tissues where it serves as house keeping gene whereas COX-2 is an inducible enzyme that is rapidly transcribed, perhaps regulated by NF-jB and other transcription factor...

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“…The growing evidence has indicated that sulindac targets nuclear β-catenin accumulation and Wnt signaling in colorectal cancers in vivo and in vitro (Boon et al, 2004;Chang et al, 2005;Gardner et al, 2004;He et al, 1999;Koornstra et al, 2005;Rice et al, 2003;Rice et al, 2006), but that sulindac targeting β-catenin in other sites is rare. Even recent report indicated that NSAIDs inhibition of β-catenin required the high level expression of peroxisome proliferators-activated receptor γ (PPAR-γ) and its co-receptor retinoid-X-receptor α (RXR-α) (Lu et al, 2005), how they are interacting to the response to NSAIDs remains unclear and needs further investigation.…”

Section: Discussionmentioning

confidence: 99%

Sulindac suppresses β-catenin expression in human cancer cells

Han

Song

Tong

et al. 2008

European Journal of Pharmacology

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Sulindac has been reported to be effective in suppressing tumor growth through the induction of p21WAF1/cip1 in human, animal models of colon cancer and colon cancer cells. In this study, we treated human breast cancer cell line MCF-7 and lung cancer cell line A549 as well as colon cancer cell line SW620 with sulindac to observe the effects of sulindac in other tissue sites. In all cell lines, proliferation was significantly inhibited by sulindac after 24 and 72 h of treatment. Apoptosis was induced by sulindac in both lung cancer cells and colon cancer cells but was not induced in breast cancer cells. Western blots showed that p21 protein level were induced by sulindac in lung cancer cells and colon cancer cells, but not in breast cancer cells. Most importantly, the suppression of β-catenin, a key mediator of Wnt signaling pathway, was seen in all three cell lines with sulindac administration. Further studies revealed that transcriptional activities of β-catenin were significantly inhibited by sulindac and that the inhibition was sulindac dosage-dependent. The transcriptional targets of β-catenin, c-myc, cyclin D1 and cdk 4 were also dramatically downregulated. In conclusion, our data demonstrated that the efficacy of sulindac in the inhibition of cell proliferation (rather than the induction of apoptosis) might be through the suppression of β-catenin pathway in human cancer cells.

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Sulindac independently modulates extracellular signal–regulated kinase 1/2 and cyclic GMP–dependent protein kinase signaling pathways

Cited by 20 publications

References 17 publications

Involvement of the extracellular signal-regulated kinase 1/2 signaling pathway in amylin's eating inhibitory effect

Involvement of the extracellular signal-regulated kinase 1/2 signaling pathway in amylin's eating inhibitory effect

A novel copper complex of 3‐benzoyl‐α methyl benzene acetic acid with antitumor activity mediated via cyclooxygenase pathway

Sulindac suppresses β-catenin expression in human cancer cells

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