Sulindac sulfide inhibits Ras signaling

Herrmann, Christian; Block, Christoph; Geisen, Christoph; Haas, Kirsten; Weber, Christoph K.; Winde, Günther; Möröy, Tarik; Müller, Oliver

doi:10.1038/sj.onc.1202085

Cited by 118 publications

(82 citation statements)

References 26 publications

(37 reference statements)

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“…Sulindac sulfide at a concentration of 100 µM caused the most impressive effect. We therefore chose a concentration of 100 µM for all subsequent experiments since this concentration is also consistent with that used in previous studies (Herrmann et al 1998). We found that sulindac sulfide significantly inhibited E2-mediated VDR upregulation in both HT29 and MCF-7 cells, indicating that Ras signaling is involved in E2-mediated VDR transcriptional control.…”

Section: Sulindac Sulfide Inhibits E2-mediated Vdr Expressionmentioning

confidence: 54%

“…The ability of sulindac sulfide to inhibit Ras (Herrmann et al 1998) warrants examination whether sulindac sulfide can inhibit other pathways dependent on Ras. To that end, we incubated HT29 and MCF-7 cells with sulindac sulfide (100 µM) in the presence of E2 and tested the effect on VDR expression (Fig.…”

Section: Sulindac Sulfide Inhibits E2-mediated Vdr Expressionmentioning

confidence: 99%

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Regulation of vitamin D receptor expression via estrogen-induced activation of the ERK 1/2 signaling pathway in colon and breast cancer cells

Gilad

Bresler²,

J³

et al. 2005

Journal of Endocrinology

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We previously demonstrated that 17 -estradiol (E2) regulates the transcription and expression of the vitamin D receptor (VDR) in rat colonocytes and duodenocytes in vivo. The aim of the present study was to assess whether the extracellular signal-regulated kinase (ERK) induced by E2 is involved in regulating VDR expression. We compared E2-associated signaling activity in HT29 colon cancer cells, a non-classical E2-target, with that in MCF-7 breast cancer cells, the natural targets of the hormone. E2 did not affect proliferation of HT29 cells, but enhanced proliferation of MCF-7 cells. Vitamin D inhibited proliferation of both cell lines and the combined treatment induced potentiation of vitamin D activity. E2 upregulated VDR transcription and protein expression concomitantly with ERK 1/2 phosphorylation in both cell lines. PD98059, a specific mitogen-activated protein kinase (MAPK) inhibitor, prevented E2-mediated activation of ERK 1/2, with concomitant inhibition of VDR expression. ICI182780 inhibited VDR expression in HT29 and MCF-7 cell lines. A conjugate of E2 and bovine serum albumin upregulated phosphorylation of ERK 1/2 and concomitantly enhanced VDR expression in a similar fashion as the nonconjugated hormone. Expression of ER and ER was detected in MCF-7 and HT29 cell lines respectively, which localized to the nuclei, cytosol and caveolar membrane rather than non-caveolar membrane. Disruption of lipid rafts/caveolae by depleting cellular cholesterol with the cholesterol-binding reagentmethylcyclodextrin blocked ERK 1/2 phosphorylation concomitantly with VDR upregulation. The tyrosine phosphorylation inhibitor suramin and src kinase inhibitor PP2 inhibited both ERK 1/2 phosphorylation and VDR expression. E2 induced phosphorylation of Raf and Jun in a time-dependent manner. The Ras/Raf dependent inhibitor of transactivation sulindac sulfide also blocked E2 effects. The specific c-Jun phosphorylation inhibitor SP600125 dose dependently inhibited c-Jun phosphorylation and VDR expression. The MAPK/ERK kinase inhibitor PD 98059 downregulated both c-Jun phosphorylation and VDR expression indicating that upstream and downstream events in the signaling cascade are all related to the control of VDR expression. Taken together, our data suggest that E2 binds to receptors compartmentalized to membranal caveolar domains in HT29 and MCF-7 cells, inducing ERK 1/2 activation and transcriptional activity, which finally results in upregulation of expression of the VDR gene.

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Section: Sulindac Sulfide Inhibits E2-mediated Vdr Expressionmentioning

confidence: 54%

Section: Sulindac Sulfide Inhibits E2-mediated Vdr Expressionmentioning

confidence: 99%

Regulation of vitamin D receptor expression via estrogen-induced activation of the ERK 1/2 signaling pathway in colon and breast cancer cells

Gilad

Bresler²,

J³

et al. 2005

Journal of Endocrinology

View full text Add to dashboard Cite

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“…Moreover, the caspase inhibitor zVAD-fmk suppressed cell death, Bax was noted to translocate from the cytosol to mitochondria, and cytochrome c release from mitochondria was seen using time-lapse confocal microscopy (Zimmermann et al, 2000). Sulindac sulfide (up to 500 µM tested) can inhibit growth of NIH3T3 and SAOS cells: an inhibtion of ras mediated proliferation and transformation was noted (Herrmann et al, 1998). Hughes et al, (2003) showed that NSAID treatment of colorectal cancer cell lines caused a decrease in intracellular polyamine content and was cytotoxic.…”

Section: Nsaids Signalling Pathways and Apoptosismentioning

confidence: 98%

Non-Steroidal Anti-Inflammatory Drugs, DNA Repair and Cancer

Dibra¹,

Perry²,

Nicholl³

2011

DNA Repair and Human Health

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“…Several lines of evidence suggest that some of the effects of NSAIDs are independent of the inhibition of COX (23). Indeed, it has been shown that NSAIDs modulate COX-independent signaling pathways, such as Ras (24), NFB (25), activator protein-1 (26), ERK (26), p38 kinase (27), and others. Because the role of NSAIDs in the maintenance of homeostasis and apoptosis of articular chondrocytes is not clearly understood, although the action of NSAIDs in inflammation is clear, we investigated the function of various NSAIDs in NO-induced dedifferentiation and apoptosis and characterized the molecular mechanism of NSAIDs action in articular chondrocytes.…”

mentioning

confidence: 99%

Non-steroidal Anti-inflammatory Drugs Inhibit Nitric Oxide-induced Apoptosis and Dedifferentiation of Articular Chondrocytes Independent of Cyclooxygenase Activity

Yoon

Kim

Hwang

et al. 2003

Journal of Biological Chemistry

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Nitric oxide (NO) causes apoptosis and dedifferentiation of articular chondrocytes by the modulation of extracellular signal-regulated kinase (ERK), p38 kinase, and protein kinase C (PKC) ␣ and -. In this study, we investigated the effects and mechanisms of non-steroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, ketoprofen, ibuprofen, sulindac sulfide, and flurbiprofen, in NO-induced apoptosis and dedifferentiation of articular chondrocytes. We found that all of the examined NSAIDs inhibited apoptosis and dedifferentiation. NO production in chondrocytes caused activation of ERK-1/2 and p38 kinase, which oppositely regulate apoptosis and dedifferentiation. NO production also caused inhibition of PKC␣ and -independent of and dependent on, respectively, p38 kinase, which is required for apoptosis and dedifferentiation. Among the signaling molecules modulated by NO, NSAIDs blocked NO-induced activation of p38 kinase, potentiated ERK activation, and blocked inhibition of PKC␣ and -. NSAIDs also inhibited some of the apoptotic signaling that is downstream of p38 kinase and PKC, such as NFB activation, p53 accumulation, and caspase-3 activation. The inhibitory effects of NSAIDs on apoptosis and dedifferentiation were independent of the inhibition of cyclooxygenase (COX)-2 and prostaglandin E 2 (PGE 2 ) production, as evidenced by the observation that specific inhibition of COX-2 activity and PGE 2 production or exogenous PGE 2 did not affect NO-induced apoptosis and dedifferentiation. Taken together, our results indicate that NSAIDs block NO-induced apoptosis and dedifferentiation of articular chondrocytes by the modulation of ERK, p38 kinase, and PKC␣ and -in a manner independent of their ability to inhibit COX-2 and PGE 2 production.Chondrocytes are a unique cell type in which the differentiated phenotype is reversible. The phenotype of chondrocytes is regulated by the balance between anabolic and catabolic reactions of molecules, which are involved in the maintenance of cartilage homeostasis (1). Differentiated chondrocytes both in vivo and in vitro dedifferentiate into fibroblastic cells upon exposure to interleukin-1␤ (2, 3), retinoic acid (4), or nitric oxide (NO) 1 (5). Although the molecular mechanism is not yet clear, dedifferentiation of articular chondrocytes is believed to play a role in the pathophysiology of arthritis. In addition to dedifferentiation, increased apoptotic death of chondrocytes was observed in arthritic cartilage, and apoptosis is closely related to cartilage destruction (6, 7), indicating that chondrocyte apoptosis plays an important role in the pathogenesis of arthritis.NO is generally believed to be an important mediator of the dedifferentiation and apoptosis of articular chondrocytes in arthritic cartilage (5,8,9). NO is produced in chondrocytes by the action of proinflammatory cytokines, such as interleukin-1␤. NO production in chondrocytes causes activation of matrix metalloproteinases (10), decreased production of interleukin-1 receptor antagonists (11), inhibition of ...

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Sulindac sulfide inhibits Ras signaling

Cited by 118 publications

References 26 publications

Regulation of vitamin D receptor expression via estrogen-induced activation of the ERK 1/2 signaling pathway in colon and breast cancer cells

Regulation of vitamin D receptor expression via estrogen-induced activation of the ERK 1/2 signaling pathway in colon and breast cancer cells

Non-Steroidal Anti-Inflammatory Drugs, DNA Repair and Cancer

Non-steroidal Anti-inflammatory Drugs Inhibit Nitric Oxide-induced Apoptosis and Dedifferentiation of Articular Chondrocytes Independent of Cyclooxygenase Activity

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