Nitric Oxide Is a Key Component in Inflammation-Accelerated Tumorigenesis

Hussain, S. Perwez; He, Peijun; Subleski, Jeffrey; Hofseth, Lorne J.; Trivers, Glennwood E.; Mechanic, Leah E.; Hofseth, Anne B.; Bernard, Mark; Schwank, Jonathan; Nguyen, Giang Huong; Mathé, Ewy A.; Djurickovic, Draginja; Haines, Diana C.; Weiss, Jonathan M.; Back, Timothy C.; Gruys, Eilene; Laubach, Victor E.; Wiltrout, Robert H.; Harris, Curtis C.

doi:10.1158/0008-5472.can-08-0410

Cited by 98 publications

(84 citation statements)

References 49 publications

(61 reference statements)

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“…There is now strong evidence that NO itself, through its proinflammatory effects, may play an important role in carcinogenesis (35). The increase in iNOS activity may well be a consequence of the proinflammatory environment in the colon of Gstp-null Apc Min mice.…”

Section: Discussionmentioning

confidence: 99%

Markedly enhanced colon tumorigenesis in Apc ^Min mice lacking glutathione S-transferase Pi

Ritchie

Walsh

Sansom

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Glutathione transferases are a multigene family of proteins that catalyze the conjugation of toxic electrophiles and carcinogens to glutathione. Glutathione transferase Pi (GSTP) is commonly overexpressed in human tumors and there is emerging evidence that the enzyme has additional cellular functions in addition to its role in drug and carcinogen detoxification. To investigate the unique functions of this enzyme, we have crossed Gstp null mice with an initiated model of colon cancer, the Apc Min mouse. In contrast to the Apc Min/؉ Gstp1/p2 ؉/؉ (Gstp-wt Apc Min ) mice, which rarely develop colonic tumours, Apc Min/؉ Gstp1/p2 ؊/؊ (Gstp-null Apc Min ) mice had a 6-fold increase in colon adenoma incidence, and a 50-fold increase in colorectal adenoma multiplicity, relative to Gstp-wt Apc Min . This increase was associated with early tumor onset and decreased survival. Analysis of the biochemical changes in the colon tissue of Gstp-null Apc Min mice demonstrated a marked induction of many inflammatory genes, including IL-6, IL-4, IFN-␥, and inducible nitric oxide synthase. In support of the induction of inducible nitric oxide synthase, a profound induction of nitrotyrosine adducts was observed. Gstp therefore appears to play a role in controlling inflammatory responses in the colon, which would explain the change in tumor incidence observed. These data also suggest that individual variation in GSTP levels may be a factor in colon cancer susceptibility.cancer ͉ colorectal ͉ inflammation G lutathione S-transferases play a key role in chemical detoxification by catalyzing the conjugation of reduced glutathione to reactive electrophiles (1). In a genetic approach to study GST functions, we have generated mice nulled at the glutathione transferase Pi (GSTP) Gstp gene locus (2). These mice develop normally, are fertile, and show no obvious abnormalities. Topical application of the tumor initiator 7,12-dimethylbenz[a]anthracene, followed by the promoting agent 12-0-tetradecanoylphorbol-13-acetate, resulted in a significant increase in the number of papillomas in null animals (2). Similarly, increased adenoma formation in the lungs of Gstp-null mice relative to wild-type mice was also observed following dosing with benzo[a]pyrene, 3-methylcholanthene and urethane (3). In recent studies we have obtained evidence that this protein can also modulate toxicological or carcinogenic response in a manner distinct from its role in chemical detoxification (4). Further evidence of unique GSTP function is demonstrated by its ability to form protein-protein interactions and regulate the activities of several cellular proteins (JNK and TRAF2) independently of its catalytic function (5, 6). GSTP has also been shown to potentiate S-glutathionylation reactions following oxidative and nitrosative stress in vitro and in vivo (7).To further evaluate the role of GSTP in disease processes, we have investigated whether GSTP can alter colon cancer susceptibility in the Apc Min mouse. Mutations in the Apc gene is a major initiating factor in the aet...

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Section: Discussionmentioning

confidence: 99%

Markedly enhanced colon tumorigenesis in Apc ^Min mice lacking glutathione S-transferase Pi

Ritchie

Walsh

Sansom

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Higher levels of NO· can be produced by an inducible nitric oxide synthase (iNOS, also known as NOS2) in different cell types, but mainly in macrophages, upon infection to kill pathogens (reviewed in reference 9). The higher levels of NO· produced by iNOS have been implicated in various human inflammatory diseases and neurodegenerative diseases (reviewed in references 9 and 12) and in chronic inflammation-related tumorigenesis (18,33). Recent studies have also shown that chemical-generated higher levels of exogenous NO· can induce tumor cell apoptosis in vitro and in animal studies (37; reviewed in reference 1), raising interests in therapeutic exploration of NO·-releasing reagents as antitumor prodrugs.…”

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confidence: 99%

Bacterium-Generated Nitric Oxide Hijacks Host Tumor Necrosis Factor Alpha Signaling and Modulates the Host Cell Cycle In Vitro

Mocca

Wang

2012

J Bacteriol

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In mammalian cells, nitric oxide (NO·) is an important signal molecule with concentration-dependent and often controversial functions of promoting cell survival and inducing cell death. An inducible nitric oxide synthase (iNOS) in various mammalian cells produces higher levels of NO· from L-arginine upon infections to eliminate pathogens. In this study, we reveal novel pathogenic roles of NO· generated by bacteria in bacterium-host cell cocultures using Moraxella catarrhalis, a respiratory tract disease-causing bacterium, as a biological producer of NO·. We recently demonstrated that M. catarrhalis cells that express the nitrite reductase (AniA protein) can produce NO· by reducing nitrite. Our study suggests that, in the presence of pathophysiological levels of nitrite, this opportunistic pathogen hijacks host cell signaling and modulates host gene expression through its ability to produce NO· from nitrite. Bacterium-generated NO· significantly increases the secretion of tumor necrosis factor alpha (TNF-␣) and modulates the expression of apoptotic proteins, therefore triggering host cell programmed death partially through TNF-␣ signaling. Furthermore, our study reveals that bacterium-generated NO· stalls host cell division and directly results in the death of dividing cells by reducing the levels of an essential regulator of cell division. This study provides unique insight into why NO· may exert more severe cytotoxic effects on fast growing cells, providing an important molecular basis for NO·-mediated pathogenesis in infections and possible therapeutic applications of NO·-releasing molecules in tumorigenesis. This study strongly suggests that bacterium-generated NO· can play important pathogenic roles during infections. In mammalian cells, nitric oxide (NO·) is a highly reactive and diffusible signaling molecule that plays key roles in modulating both physiological and pathological processes, such as immune response, cell survival, and cell death (reviewed in references 8 and 36). The diverse functions of NO· are often determined by its concentration or its source of production. Low levels of endogenous NO· are produced from L-arginine by constitutively expressed nitric oxide synthase in neuronal cells (nNOS, also known as NOS1) and endothelial cells (eNOS, also known as NOS3) to mediate normal physiological processes. Higher levels of NO· can be produced by an inducible nitric oxide synthase (iNOS, also known as NOS2) in different cell types, but mainly in macrophages, upon infection to kill pathogens (reviewed in reference 9). The higher levels of NO· produced by iNOS have been implicated in various human inflammatory diseases and neurodegenerative diseases (reviewed in references 9 and 12) and in chronic inflammation-related tumorigenesis (18, 33). Recent studies have also shown that chemical-generated higher levels of exogenous NO· can induce tumor cell apoptosis in vitro and in animal studies (37; reviewed in reference 1), raising interests in therapeutic exploration of NO·-releasing reagents as antitumor...

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“…It is claimed that p53 À / À NOS2 þ / þ C57BL/6 mice, which display greater NO production, experience accelerated spontaneous tumor development, compared with p53 À / À NOS2 À / À mice. 65 In contrast, increased iNOS expression was also reported to be cytotoxic for tumor cells, since accumulated NO would trigger p53-mediated growth arrest and apoptosis. 66 With the guardian p53 absence, accumulated NO would impair T-cell function and, in turn, facilitate tumor progression.…”

Section: Discussionmentioning

confidence: 99%

p53 regulates mesenchymal stem cell-mediated tumor suppression in a tumor microenvironment through immune modulation

Huang

et al. 2013

Oncogene

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p53 is one of the most studied genes in cancer biology, and mutations in this gene may be predictive for the development of many types of cancer in humans and in animals. However, whether p53 mutations in non-tumor stromal cells can affect tumor development has received very little attention. In this study, we show that B16F0 melanoma cells form much larger tumors in p53-deficient mice than in wild-type mice, indicating a potential role of p53 deficiency in non-tumor cells of the microenvironment. As mesenchymal stem cells (MSCs) are attracted to tumors and form a major component of the tumor microenvironment, we examined the potential role of p53 status in MSCs in tumor development. We found that larger tumors resulted when B16F0 melanoma cells were co-injected with bone marrow MSCs derived from p53-deficient mice rather than MSCs from wild-type mice. Interestingly, this tumor-promoting effect by p53-deficient MSCs was not observed in non-obese diabetic/severe combined immunodeficiency mice, indicating the immune response has a critical role. Indeed, in the presence of inflammatory cytokines, p53-deficient MSCs expressed more inducible nitric oxide synthase (iNOS) and exhibited greater immunosuppressive capacity. Importantly, tumor promotion by p53-deficient MSCs was abolished by administration of S-methylisothiourea, an iNOS inhibitor. Therefore, our data demonstrate that p53 status in tumor stromal cells has a key role in tumor development by modulating immune responses.

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Nitric Oxide Is a Key Component in Inflammation-Accelerated Tumorigenesis

Cited by 98 publications

References 49 publications

Markedly enhanced colon tumorigenesis in Apc ^Min mice lacking glutathione S-transferase Pi

Markedly enhanced colon tumorigenesis in Apc ^Min mice lacking glutathione S-transferase Pi

Bacterium-Generated Nitric Oxide Hijacks Host Tumor Necrosis Factor Alpha Signaling and Modulates the Host Cell Cycle In Vitro

p53 regulates mesenchymal stem cell-mediated tumor suppression in a tumor microenvironment through immune modulation

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Nitric Oxide Is a Key Component in Inflammation-Accelerated Tumorigenesis

Cited by 98 publications

References 49 publications

Markedly enhanced colon tumorigenesis in Apc Min mice lacking glutathione S-transferase Pi

Markedly enhanced colon tumorigenesis in Apc Min mice lacking glutathione S-transferase Pi

Bacterium-Generated Nitric Oxide Hijacks Host Tumor Necrosis Factor Alpha Signaling and Modulates the Host Cell Cycle In Vitro

p53 regulates mesenchymal stem cell-mediated tumor suppression in a tumor microenvironment through immune modulation

Contact Info

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Markedly enhanced colon tumorigenesis in Apc ^Min mice lacking glutathione S-transferase Pi

Markedly enhanced colon tumorigenesis in Apc ^Min mice lacking glutathione S-transferase Pi