Cyclooxygenase inhibitors differentially modulate p73 isoforms in neuroblastoma

Lau, Loretta; Wolter, Jennifer; Lau, Joanne; Cheng, Lynn S.; Smith, Kristen M.; Hansford, Loen M.; Zhang, Libo; Baruchel, Sylvain; Robinson, Fiona; Irwin, Meredith S.

doi:10.1038/onc.2009.59

Cited by 31 publications

(31 citation statements)

References 34 publications

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“…Furthermore, KMBK also significantly and dose-dependently inhibited the PGE 2 production in LPS-stimulated BV-2 cells. Our data was consistent with the earlier works from our lab and elsewhere that LPS-induced increased COX-2 expression was suppressed by blue berry polyphenols and inflexin (16,41) without affecting the overall expression of COX-1. Several reports indicated that iNOS and COX-2 were induced in various types of central nervous system injuries and diseases (43,48).…”

Section: Discussionsupporting

confidence: 93%

“…In this study we observed that KMBK inhibited LPS-stimulated activation of p65 and degradation of IκB-α in a dose-dependent manner, suggesting that KMBK may block NF-κB subunit activation, thereby preventing phosphorylation and degradation of IκB-α. The evidence presented in this study agreed with data in previous published reports showing that LPS-induced significant activation of NF-κB cytokine expression and treatment with MMHD and blueberry polyphenols suppressed this activation in BV-2 cells (40,41).…”

Section: Discussionsupporting

confidence: 92%

“…In vivo and in vitro studies demonstrated that the prostanoids synthesizing enzyme COX-2 was markedly upregulated in microglia in rodent brain and in BV-2 cells after LPS treatment (19,41,42). Increased expression of the COX-2 enzyme and elevated levels of PGE 2 occur in a variety of neurodegenerative diseases (43,44).…”

Section: Discussionmentioning

confidence: 99%

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Anti-neuroinflammatory Activity of Kamebakaurin From Isodon japonicus via Inhibition of c-Jun NH2-Terminal Kinase and p38 Mitogen-Activated Protein Kinase Pathway in Activated Microglial Cells

et al. 2011

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Abstract.Compelling evidence supports the notion that the majority of neurodegenerative diseases are associated with microglia-mediated neuroinflammation. Therefore, quelling of microglial activation may lead to neuronal cell survival. The present study investigated the effects of Kamebakaurin (KMBK), a kaurane diterpene isolated from Isodon japonicus HARA (Labiatae), on the production of pro-inflammatory mediators in lipopolysaccharide (LPS)-stimulated cytotoxicity in rat primary microglial cultures and the BV-2 cell line. KMBK significantly inhibited the LPSinduced production of nitric oxide (NO) in a concentration-dependent fashion in activated microglial cells. The mRNA and protein levels of inducible nitric oxide synthase (iNOS) and cyclooxycenase-2 (COX-2) were also decreased dose-dependently. Furthermore KMBK inhibited the JNK and p38 mitogen-activated protein kinases (MAPKs) in LPS-stimulated BV-2 microglial cells. Considering the results obtained, the present study authenticated the potential benefits of KMBK as a therapeutic target in ameliorating microglia-mediated neuroinflammatory diseases.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 92%

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Anti-neuroinflammatory Activity of Kamebakaurin From Isodon japonicus via Inhibition of c-Jun NH2-Terminal Kinase and p38 Mitogen-Activated Protein Kinase Pathway in Activated Microglial Cells

et al. 2011

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“…It might be worth mentioning that an important class of drugs, cyclooxygenase inhibitors, has recently been shown to induce apoptosis independent of p53 and differentially modulate endogenous TAp73 and ΔNp73 isoforms in fresh neuroblastoma cells (85). Cyclooxygenase downregulation of ΔNp73 is associated with decreased levels of transcription factor E2F-1.…”

Section: Targeting P73: a Promising Antitumor Strategy?mentioning

confidence: 99%

The p53 Family Protein p73 Provides New Insights into Cancer Chemosensitivity and Targeting

Lunghi

Costanzo

Mazzera

et al. 2009

Clinical Cancer Research

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The p53 tumor suppressor is part of a small family of related proteins that includes two other members, p73 and p63. Interest in the p53 family members, their functions and their complex interactions and regulation, has steadily grown over recent years and does not show signs of waning. p73 is a major determinant of chemosensitivity in humans, and mutant p53 proteins carrying specific polymorphisms can induce drug resistance by inhibiting TAp73. Cooperation between TA (transactivating, proapoptotic, antiproliferative) and ΔN (truncated, antiapoptotic, pro-proliferative) p73 isoforms and among the three family members guarantees equilibrium between proliferation, differentiation, and cell death, thus creating a harmony that is lost in several human cancers. In this article, we review our current knowledge of the role of p73 in cancer chemosensitivity and the real prospect of therapy targeting this molecule. We also draw attention to the crucial role of specific phosphorylation and acetylation events for p73-induced apoptosis and drug chemosensitivity. ( The p53 tumor suppressor (1, 2) belongs to a small family of related proteins that includes two other members, p73 and p63, discovered in 1997 (3) and 1998 (4-7), respectively.This review, after a brief introduction on evolution within the p53 family, has two primary aims: to focus on the crucial role of p73 in cancer chemosensitivity and to discuss the prospect of cancer treatment targeting this molecule. Despite the translational focus of this review, however, the end purpose of a CCR Review precludes citing all contributions and all contributors, for which we apologize in advance. Evolution within the p53 FamilyOverall structure and sequence homology indicate that p63, p73, and p53 evolved from a common ancestor (8). p73 and p63 share hallmark features that identify p53 across species from Drosophila melanogaster and Caenorhabditis elegans to human: an acidic NH 2 -terminal transactivation (TA) domain, a highly conserved core DNA-binding domain (DBD), and a COOH-terminal oligomerization domain (Fig. 1). Both p63 and p73 have a sterile α-motif domain implicated in protein-protein interaction. The highest degree of homology is shown within the DBD, where p63 and p73 share approximately 65% amino acidic identity with the DBD of p53 and higher identity (85%) with each other. All three genes are now known to contain a second intronic promoter that controls the expression of NH 2 -terminally truncated ΔN proteins (ΔNp73, ΔNp63, and Δ133p53; refs. 4, 9-13). Additional ΔN isoforms are generated by alternative splicing and initiation of translation (Δ40p53, Δex2p73, Δex2/3p73, and ΔN′p73) of mRNAs transcribed from the canonical upstream promoter regions (13-15). Δ40p53 and ΔN′p73 are originated by variations of the proline-rich domain. The term ΔTAp73 comprises ΔNp73, Δex2p73, Δex2/3p73, and ΔN′p73 isoforms. Because the lack of acidic NH 2 -terminal TA domain hampers activation of target genes, TA full-length isoforms (FLp53, TAp73, and TAp63) are functionally ...

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“…In this context, specific COX-2 inhibitors, such as the "coxib" family, have been tested as good candidates for cancer therapy (Sobolewski et al, 2010). Most of these molecules are strong inducers of apoptosis or slow down cell cycle in many cancer models, including hematologic malignancies (Jendrossek et al, 2003;Arunasree et al, 2008;Liu et al, 2008;Lau et al, 2009;Mutter et al, 2009;Park et al, 2010). Moreover, COX-2 inhibitors are able to sensitize tumors to chemotherapy, radiotherapy, or photodynamic therapy (Cao and Prescott, 2002;Sobolewski et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

2,5-Dimethyl-Celecoxib Inhibits Cell Cycle Progression and Induces Apoptosis in Human Leukemia Cells

Sobolewski

Rhim

Legrand

et al. 2015

J Pharmacol Exp Ther

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Cyclooxygenase-2 (COX-2) is an essential regulator of cancer promotion and progression. Extensive efforts to target this enzyme have been developed to reduce growth of cancer cells for chemopreventive and therapeutic reasons. In this context, cyclooxygenase-2 inhibitors present interesting antitumor effects. However, inhibition of COX-2 by anti-COX-2 compounds such as celecoxib was recently associated with detrimental cardiovascular side effects limiting their clinical use. As many anticancer effects of celecoxib are COX-2 independent, analogs such as 2,5-dimethyl-celecoxib (DMC), which lacks COX-2-inhibitory activity, represent a promising alternative strategy. In this study, we investigated the effect of this molecule on growth of hematologic cancer cell lines (U937, Jurkat, Hel, Raji, and K562). We found that this molecule is able to reduce the growth and induces apoptosis more efficiently than celecoxib in all the leukemic cell lines tested. Cell death was associated with downregulation of Mcl-1 protein expression. We also found that DMC induces endoplasmic reticulum stress, which is associated with a decreased of GRP78 protein expression and an alteration of cell cycle progression at the G1/S transition in U937 cells. Accordingly, typical downregulation of c-Myc and cyclin D1 and an upregulation of p27 were observed. Interestingly, for shorter time points, an alteration of mitotic progression, associated with the downregulation of survivin protein expression was observed. Altogether, our data provide new evidence about the mode of action of this compound on hematologic malignancies.

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Cyclooxygenase inhibitors differentially modulate p73 isoforms in neuroblastoma

Cited by 31 publications

References 34 publications

Anti-neuroinflammatory Activity of Kamebakaurin From Isodon japonicus via Inhibition of c-Jun NH2-Terminal Kinase and p38 Mitogen-Activated Protein Kinase Pathway in Activated Microglial Cells

Anti-neuroinflammatory Activity of Kamebakaurin From Isodon japonicus via Inhibition of c-Jun NH2-Terminal Kinase and p38 Mitogen-Activated Protein Kinase Pathway in Activated Microglial Cells

The p53 Family Protein p73 Provides New Insights into Cancer Chemosensitivity and Targeting

2,5-Dimethyl-Celecoxib Inhibits Cell Cycle Progression and Induces Apoptosis in Human Leukemia Cells

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