Relationship Between p53 Mutations and Inducible Nitric Oxide Synthase Expression in Human Colorectal Cancer

Ambs, Stefan; Bennett, W P; Merriam, William G.; Ogunfusika, Mofolusara O.; Oser, Sean M.; Harrington, A. M.; Shields, Peter G.; Felley‐Bosco, Emanuela; Hussain, S. Perwez; Harris, Curtis C.

doi:10.1093/jnci/91.1.86

Cited by 180 publications

(147 citation statements)

References 21 publications

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“…As NO -induced apoptosis can be p53 dependent, cells with mutant TP53 have a clonal expansion advantage. Consistent with this model, we have found a significant association as well as a doseresponse relationship between TP53 mutations (G:C to A:T transition at cytosine guanine dinucleotide (CpG) sites) and an increased NOS2 activity in patients with colon cancer (Ambs et al, 1999). Furthermore, we and others have demonstrated a positive association of NOS2 expression and a comparable TP53 mutational spectrum in lung cancer (Fujimoto et al, 1998;Ambs et al, 1998a).…”

Section: Figuresupporting

confidence: 87%

TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer

et al. 2007

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Section: Figuresupporting

confidence: 87%

TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer

et al. 2007

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“…If the NO released form NO-NSAIDs is to behave as a carcinogen or promoter of carcinogenesis, this would require either a prolonged exposure to NO or some crucial effect on genes whose mutation may be contribute to carcinogenesis. A rather compelling case has been described by Ambs et al [56] who studied the mutations of p53 in the vicinity of NOS and demonstrated that the NO produced through the catalytic activity of this enzyme was responsible for critical mutagenesis.…”

Section: No-nsaids As Potential Promoters Of Carcinogenesismentioning

confidence: 96%

NO-donating NSAIDs and cancer: An overview with a note on whether NO is required for their action

Rigas

Williams

2008

Nitric Oxide

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Nitric oxide-donating nonsteroidal anti-inflammatory drugs (NO-NSAIDs) consist of a conventional NSAID to which an NO-releasing moiety is attached covalently, often via a spacer molecule. NONSAIDs represent an emerging class of compounds with chemopreventive properties against a variety of cancers, demonstrated in preclinical models including cell culture systems and animal tumor models; their potential efficacy in humans has not been assessed. Their mechanism of action appears complex and involves the generation of reactive oxygen species, suppression of microsatellite instability in mismatch repair-deficient cells, and modulation of several signaling cascades that culminate in inhibited cell renewal and enhanced apoptosis. NO, long appreciated to be able to protect from and also promote cancer, is released form NO-NSAIDs and constitutes their defining property. Existing data are consistent with the notion that NO may mediate their anticancer effect. In addition there is evidence that long term administration of NO-donating compounds is not associated with increased incidence of colon cancer. Whether NO release is required for the anticancer effect of NO-NSAIDs has being questioned by recent data indicating that, at least in the case of NO-aspirin, the NO-releasing moiety may serve as a leaving group while the spacer actually being the moiety responsible for its pharmacological action. Regardless of mechanistic issues, these compounds promise to contribute to the control of cancer.

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“…28,34 Most significantly, the crosstalk between NO and p53 is likely to play an important role in tumor suppression and in carcinogenesis. [35][36][37] However, the molecular mechanisms underlying the induction of p53 by NO have not been fully elucidated. We recently reported that NO signalling to p53 is independent of ATM, PARP-1 (Poly(ADP-Ribose) Polymerase 1) and ARF.…”

Section: Introductionmentioning

confidence: 99%

Nitric oxide promotes p53 nuclear retention and sensitizes neuroblastoma cells to apoptosis by ionizing radiation

2003

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Nitric oxide (NO) is a potent activator of the p53 tumor suppressor protein. However, the mechanisms underlying p53 activation by NO have not been fully elucidated. We previously reported that a rapid downregulation of Mdm2 by NO may contribute to the early phase of p53 activation. Here we show that NO promotes p53 nuclear retention and inhibits Mdm2-mediated p53 nuclear export. NO induces phosphorylation of p53 on serine 15, which does not require ATM but rather appears to depend on the ATM-related ATR kinase. An ATRkinase dead mutant or caffeine, which blocks the kinase activity of ATR, effectively abolishes the ability of NO to cause p53 nuclear retention, concomitant with its inhibition of p53 serine 15 phosphorylation. Of note, NO enhances markedly the ability of low-dose ionizing radiation to elicit apoptotic killing of neuroblastoma cells expressing cytoplasmic wild-type p53. These findings imply that, through augmenting p53 nuclear retention, NO can sensitize tumor cells to p53-dependent apoptosis. Thus, NO donors may potentially increase the efficacy of radiotherapy for treatment of certain types of cancer.

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Relationship Between p53 Mutations and Inducible Nitric Oxide Synthase Expression in Human Colorectal Cancer

Cited by 180 publications

References 21 publications

TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer

TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer

NO-donating NSAIDs and cancer: An overview with a note on whether NO is required for their action

Nitric oxide promotes p53 nuclear retention and sensitizes neuroblastoma cells to apoptosis by ionizing radiation

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