Nitric Oxide Synthase Type 3 is Increased in Squamous Hyperplasia, Dysplasia, and Squamous Cell Carcinoma of the Head and Neck

Bentz, Brandon G.; Haines, G. Kenneth; Lingen, Mark W.; Pelzer, Harold J.; Hanson, David G.; Radosevich, James A.

doi:10.1177/000348949910800812

Cited by 40 publications

(63 citation statements)

References 28 publications

(31 reference statements)

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“…Higher concentrations of NO have been shown to be both damaging and pathologic to physiologic processes resulting in mutational events which might lead to cancer and promote progression of the tumor [6][7][8]. Our laboratory and others have shown that NO is overexpressed in many human cancers [9]. Additionally, in in vitro experiments, we have demonstrated that different cancer types such as lung [10], breast [11], and head and neck [12] may be adapted gradually to high concentrations of NO.…”

Section: Introductionmentioning

confidence: 56%

Part III. Molecular changes induced by high nitric oxide adaptation in human breast cancer cell line BT-20 (BT-20-HNO): a switch from aerobic to anaerobic metabolism

et al. 2012

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Nutrient deprivation and reactive oxygen species (ROS) play an important role in breast cancer mitochondrial adaptation. Adaptations to these conditions allow cells to survive in the stressful microenvironment of the tumor bed. This study is directed at defining the consequences of High Nitric Oxide (HNO) exposure to mitochondria in human breast cancer cells. The breast cancer cell line BT-20 (parent) was adapted to HNO as previously reported, resulting in the BT-20-HNO cell line. Both cell lines were analyzed by a variety of methods including MTT, LDH leakage assay, DNA sequencing, and Western blot analysis. The LDH assay and the gene chip data showed that BT-20-HNO was more prone to use the glycolytic pathway than the parent cell line. The BT-20-HNO cells were also more resistant to the apoptotic inducing agent salinomycin, which suggests that p53 may be mutated in these cells. Polymerase chain reaction (PCR) followed by DNA sequencing of the p53 gene showed that it was, in fact, mutated at the DNA-binding site (L194F). Western blot analysis showed that p53 was significantly upregulated in these cells. These results suggest that free radicals, such as nitric oxide (NO), pressure human breast tumor cells to acquire an aggressive phenotype and resistance to apoptosis. These data collectively provide a mechanism by which the dysregulation of ROS in the mitochondria of breast cancer cells can result in DNA damage.Keywords Breast cancer . Nitric oxide . p53 . Reactive oxygen species (ROS) . Glycolysis and apoptosis . Aerobic and anaerobic metabolisms

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Section: Introductionmentioning

confidence: 56%

Part III. Molecular changes induced by high nitric oxide adaptation in human breast cancer cell line BT-20 (BT-20-HNO): a switch from aerobic to anaerobic metabolism

et al. 2012

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“…As indicated in our prior works, a number of tumor cell lines have been adapted to HNO concentration levels including those from lung [11,[46][47][48], head and neck [3,[49][50][51][52], and breast [7], suggesting that NO adaptation is also a universal property. In an attempt to further elucidate the impact of extended exposure from NO on underlying biological systems, we herein characterize the four newly The ten most up-regulated appear first and the ten most down-regulated appear below within each cell line type NA not available a Gene symbols used vary according to the supplier of the gene chip created breast adenocarcinoma HNO cell lines [7], along with each respective parent cell line.…”

Section: Resultsmentioning

confidence: 85%

“…We have previously shown that together with the expression of eNOS, the expression of GSTpi also increases as carcinogenesis progresses in head and neck squamous cell carcinomas [3,53]. The expression/ amplification of GST-pi has been linked to chemotherapy resistance [54] and to decreased survival after neoadjuvant treatment [55], which at first may seem counterintuitive until one factors in that many chemotherapeutic agents work through free radicals.…”

Section: Resultsmentioning

confidence: 99%

“…Regardless of how patients present (e.g., with varying degrees of tumor size, stage, histological grade, and hormone receptor status), there is a broad array of disease outcomes from these morphologically identical tumors. It has been proposed that these varying outcomes are the result of variations in the tumor microenvironment [3][4][5]. The tumor microenvironment may further cause genetic alterations that affect tumor evolution and growth patterns, which ultimately impacts responses to therapeutic regimes and altering outcomes [3].…”

Section: Introductionmentioning

confidence: 99%

“…NO is produced by various iso-enzymes of NOS, and as NOS expression increases, so do other NO related metabolic constitutions such as nitrotryosine. These NO byproducts appear in a variety of human tumors including breast cancer [3,9,10,16,18,19,21], and in tumor-infiltrating macrophages, endothelial cells, and/or tumor cells [22,23]. By example, in a large (n0161) study of breast tumors, 61 % were found to express iNOS, and within that group, iNOS up-regulation was a marker for tumor progression.…”

Section: Introductionmentioning

confidence: 99%

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Part I. Molecular and cellular characterization of high nitric oxide-adapted human breast adenocarcinoma cell lines

et al. 2012

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There is a lack of understanding of the casual mechanisms behind the observation that some breast adenocarcinomas have identical morphology and comparatively different cellular growth behavior. This is exemplified by a differential response to radiation, chemotherapy, and other biological intervention therapies. Elevated concentrations of the free radical nitric oxide (NO), coupled with the upregulated enzyme nitric oxide synthase (NOS) which produces NO, are activities which impact tumor growth. Previously, we adapted four human breast cancer cell lines: BT-20, Hs578T, T-47D, and MCF-7 to elevated concentrations of nitric oxide (or high NO [HNO]). This was accomplished by exposing the cell lines to increasing levels of an NO donor over time. Significantly, the HNO cell lines grew faster than did each respective ("PARENT") cell line even in the absence of NO donor-supplemented media. This was evident despite each "parent" being morphologically equivalent to the HNO adapted cell line. Herein, we characterize the HNO cells and their biological attributes against those of the parent cells. Pairs of HNO/parent cell lines were then analyzed using a number of key cellular activity criteria including: cell cycle distribution, DNA ploidy, response to DNA damage, UV radiation response, X-ray radiation response, and the expression of significant cellular enzymes. Other key enzyme activities studied were NOS, p53, and glutathione S-transferase-pi (GST-pi) expression. HNO cells were typified by a far more aggressive pattern of growth and resistance to various treatments than the corresponding parent cells. This was evidenced by a higher S-phase percentage, variable radioresistance, and up-regulated GST-pi and p53. Taken collectively, this data provides evidence that cancer cells subjected to HNO concentrations become resistant to free radicals such as NO via up-regulated cellular defense mechanisms, including p53 and GST-pi. The

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Increased protein nitrosylation in head and neck squamous cell carcinogenesis

2000

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Background Nitric oxide (NO·) and its metabolic byproducts are implicated in carcinogenesis. We examined a marker of NO·‐species' pathologic protein nitrosylation, nitrotyrosine, during head and neck squamous cell carcinoma (HNSCCa) development. Materials and Methods Paraffin‐embedded tissue samples of normal oral mucosa, squamous hyperplasia/dysplasia, and HNSCCa were immunohistochemically analyzed for staining intensity using an antinitrotyrosine monoclonal antibody, and correlated with retrospective clinical data. Results Significantly higher staining was noted in reactive, dysplastic and HNSCCa samples compared with samples of normal mucosa. Additionally, significant differences in staining were found between various primary sites of the upper aerodigestive tract. Lastly, individual inflammatory cells also stained intensely. Conclusions Increasing amounts of nitrotyrosine staining were found in reactive/dysplastic and HNSCCa lesions compared to normal squamous mucosa. Inflammatory cell staining implicates NO· as a possible mediator of immunosuppression. Given these findings, the role of NO· in mutations leading to and the immunosuppression found in HNSCCa warrants further investigation. © 2000 John Wiley & Sons, Inc. Head Neck 22: 64–70, 2000.

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Nitric Oxide Synthase Type 3 is Increased in Squamous Hyperplasia, Dysplasia, and Squamous Cell Carcinoma of the Head and Neck

Cited by 40 publications

References 28 publications

Part III. Molecular changes induced by high nitric oxide adaptation in human breast cancer cell line BT-20 (BT-20-HNO): a switch from aerobic to anaerobic metabolism

Part III. Molecular changes induced by high nitric oxide adaptation in human breast cancer cell line BT-20 (BT-20-HNO): a switch from aerobic to anaerobic metabolism

Part I. Molecular and cellular characterization of high nitric oxide-adapted human breast adenocarcinoma cell lines

Increased protein nitrosylation in head and neck squamous cell carcinogenesis

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