Nitric oxide suppression triggers apoptosis through the FKHRL1 (FOXO3A)/ROCK kinase pathway in human breast carcinoma cells

Radisavljevic, Zivotije

doi:10.1002/cncr.10081

Cited by 36 publications

(74 citation statements)

References 26 publications

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“…Also, transforming growth factor ␤2 was shown to be a transcriptional target of FoxO3a in breast and pancreatic tumor cell lines (29). FoxO3a has also been shown to modulate apoptosis in response to nitric oxide suppression; however, this is mediated by Rho-associated kinase (ROCK) kinase independently of PKB (30). Consequently, the data shown here represent the first direct demonstration that FoxO3a can induce the expression of Bim and mediate apoptosis in breast cancer cells.…”

Section: Discussionmentioning

confidence: 69%

FoxO3a Transcriptional Regulation of Bim Controls Apoptosis in Paclitaxel-treated Breast Cancer Cell Lines

Sunters

Mattos

Ståhl

et al. 2003

Journal of Biological Chemistry

463

389

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Paclitaxel is used to treat breast cancers, but the mechanisms by which it induces apoptosis are poorly understood. Consequently, we have studied the role of the FoxO transcription factors in determining cellular response to paclitaxel. Western blotting revealed that in a panel of nine breast cancer cell lines expression of FoxO1a and FoxO3a correlated with the expression of the pro-apoptotic FoxO target Bim, which was associated with paclitaxel-induced apoptosis. In MCF-7 cells, which were paclitaxel-sensitive, the already high basal levels of FoxO3a and Bim protein increased dramatically after drug treatment, as did Bim mRNA, which correlated with apoptosis induction. This was not observed in MDA-231 cells, which expressed low levels of FoxOs and Bim. Gene reporter experiments demonstrated that in MCF-7 cells maximal induction of Bim promoter was dependent on a FoxO binding site, suggesting that FoxO3a is responsible for the transcriptional up-regulation of Bim. Gene silencing experiments showed that small interference RNA (siRNA) specific for FoxO3a reduced the levels of FoxO3a and Bim protein as well as inhibited apoptosis in paclitaxel-treated MCF-7 cells. Furthermore, siRNA specific for Bim reduced the levels of Bim protein and inhibited apoptosis in paclitaxel-treated MCF-7 cells. This is the first demonstration that up-regulation of FoxO3a by paclitaxel can result in increased levels of Bim mRNA and protein, which can be a direct cause of apoptosis in breast cancer cells.Breast cancer is one of the most common malignancies affecting women in the western world and arises following the accumulation of a series of somatic changes that serve to increase the rate of cellular proliferation and/or reduce the levels of apoptosis. These changes are often found to involve deregulation of key signal transduction pathways. Signal transduction pathways within the cell transmit the extracellular signals to transcription factors, resulting in changes in gene expression. These changes in gene expression are often cell typespecific and lead to cell growth, differentiation, or apoptosis, thereby regulating normal tissue structure and function. One key signal transduction pathway highly conserved in eukaryotes is the phosphatidylinositol 3-kinase (PI3K) 1 pathway (1), which is stimulated by a number of growth factors, including insulin and insulin-like growth factor 1 (1). Once a receptor tyrosine kinase has become activated by binding a specific ligand, it becomes autophosphorylated and binds PI3K heterodimers either directly, or indirectly via insulin receptor substrate (IRS) adaptor proteins (1-3). The interaction between the p85 regulatory subunit of PI3K and the receptor brings the catalytic domain (p110 subunit) of PI3K into contact with the plasma membrane, where it is able to phosphorylate its targets. Alternatively, PI3K can be juxtaposed to the plasma membrane via interactions with activated RAS family members. PI3K phosphorylates phosphatidylinositol (4,5)-diphosphate at the 3 position, resulting in the formatio...

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Section: Discussionmentioning

confidence: 69%

FoxO3a Transcriptional Regulation of Bim Controls Apoptosis in Paclitaxel-treated Breast Cancer Cell Lines

Sunters

Mattos

Ståhl

et al. 2003

Journal of Biological Chemistry

463

389

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“…The most definitive studies have been done with human colon carcinoma cells 117 , human cholangiocarcinoma cells 118 , human breast carcinoma cells 119 , and human melanoma cells 23 . Kim and Tannenbaum utilized HT-29 colon carcinoma cells to show that S-nitrosylation of procaspase-9 was the key event that protected these cells from TNFα plus interferon γ (TNFα/Ifnγ) induced apoptosis 117 .…”

Section: S-nitrosylation Inhibition Of Apoptosis In Cancer Cellsmentioning

confidence: 99%

“…Utilizing T46D human breast carcinoma cells Radisavljevic 119 demonstrated that inhibition of iNOS using N G -monomethyl-L-arginine caused enhanced apoptosis. Apoptosis signaling was shown to be independent of caspase-3 as well as the PI3K/AKT pathway.…”

Section: S-nitrosylation Inhibition Of Apoptosis In Cancer Cellsmentioning

confidence: 99%

Nitric Oxide and Cancer Development

et al. 2007

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Abstract:The role of nitric oxide (NO) in cancer development has become a very active research area. This review presents an overview of many studies that implicate an important role of NO in the development of cancer. These include results in experimental models as well as many observations made on NO and inducible nitric oxide synthase (iNOS) in human cancers. Our survey of the literature has allowed us to conclude that in general large levels of NO will kill cancer cells but paradoxically at intermediate to lower levels NO prevents cancer cell apoptosis and enhances tumor growth. This basic tenet has been demonstrated in many experimental models. The mechanistic basis of how intermediate levels of NO mediate tumor development is an active area of research and is the subject of this review. NO mediated S-nitrosylation of key enzymes and regulatory proteins plays a critical role. Key proteins S-nitrosylated which enhance tumor development include several caspases involved in apoptosis, PTEN the tumor suppressor protein, Bcl-2 the mitochondrial protein which protects from apoptosis, OGG1 the DNA repair protein and methionine adenosyl transferase the liver protein which synthesizes adenosylmethionine. The S-nitrosylation of these proteins enhances DNA mutations, prevents cancer cell apoptosis and enhances oncogenic cell growth. (J Toxicol Pathol 2007; 20: 77-92)

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“…Therefore the lack of NO is associated with apoptosis of these cells or, stated another way, the presence of NO prevents the apoptosis of preneoplastic liver cells. Several studies of livers containing tumors (Salvucci et al, 2001;Torok et al, 2002;Radisavljevic, 2003), as well as of isolated hepatocytes (Kim et al, 1997a(Kim et al, , 1997b(Kim et al, , 2000 demonstrate that NO prevents apoptosis by forming critical S-nitrosylation bonds which inactivate specific caspases, probably caspase 8 (Kim et al, 2000) or 9, thereby inactivating them and preventing the initiation of apoptosis. In addition to this antiapoptotic role of NO, there are several other critical enzymes which NO can inactivate to promote cancer development.…”

Section: Anticancer Activity Of Nitronesmentioning

confidence: 99%

Nitrones as therapeutics in age‐related diseases

Floyd

2006

Aging Cell

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SummaryAge-related diseases deprive individuals of a higher quality of life and therefore therapeutics for their treatment provide significant potential. An overview of the observations of nitrones as potential therapeutics in several age-related diseases is presented. Treatment of acute ischemic stroke is one condition where a nitrone (NXY-059) is in late phase 3 clinical trials now. Also presented is a summary of the most recent work we have accomplished on the anticancer activity of the nitrones in a hepatocellular carcinoma. The mechanistic basis of action of these compounds in several animal models is not yet understood at the molecular levels; however, it does appear clear that their anti-inflammatory properties are central to their action, which is based on their ability to down-regulate exacerbated signal transduction processes.

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Nitric oxide suppression triggers apoptosis through the FKHRL1 (FOXO3A)/ROCK kinase pathway in human breast carcinoma cells

Cited by 36 publications

References 26 publications

FoxO3a Transcriptional Regulation of Bim Controls Apoptosis in Paclitaxel-treated Breast Cancer Cell Lines

FoxO3a Transcriptional Regulation of Bim Controls Apoptosis in Paclitaxel-treated Breast Cancer Cell Lines

Nitric Oxide and Cancer Development

Nitrones as therapeutics in age‐related diseases

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