Long-Term Nitric Oxide Exposure Enhances Lung Cancer Cell Migration

Sanuphan, Arpasinee; Chunhacha, Preedakorn; Pongrakhananon, Varisa; Chanvorachote, Pithi

doi:10.1155/2013/186972

Cited by 37 publications

(32 citation statements)

References 35 publications

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“…Previous studies indicated that NO could render cells resistant to death induced by various stimuli (7,8,67). NO also regulates cancer cell migration and invasion (60), and increased NOS expression and activity have been reported in metastatic lung cancer cells (57). Clinical data further support the role of NO in lung cancer and metastasis.…”

mentioning

confidence: 65%

“…Elevated NO levels have been associated with cancer cell behaviors such as anoikis resistance, increased cell motility, and chemoresistance (8,60,67). To test whether NO might affect epithelial-mesenchymal transition (EMT) properties of lung cancer cells, we first determined the appropriate noncytotoxic concentrations of NO donor used in this study.…”

Section: Effect Of Dpta Nonoate On Human Lung Cancer Cell Epithelial-mentioning

confidence: 99%

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Nitric oxide induces cancer stem cell-like phenotypes in human lung cancer cells

Yongsanguanchai

Pongrakhananon

Mutirangura

et al. 2015

American Journal of Physiology-Cell Physiology

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Yongsanguanchai N, Pongrakhananon V, Mutirangura A, Rojanasakul Y, Chanvorachote P. Nitric oxide induces cancer stem cell-like phenotypes in human lung cancer cells. Am J Physiol Cell Physiol 308: C89 -C100, 2015. First published November 19, 2014; doi:10.1152/ajpcell.00187.2014.-Even though tremendous advances have been made in the treatment of cancers during the past decades, the success rate among patients with cancer is still dismal, largely because of problems associated with chemo/radioresistance and relapse. Emerging evidence has indicated that cancer stem cells (CSCs) are behind the resistance and recurrence problems, but our understanding of their regulation is limited. Rapid reversible changes of CSC-like cells within tumors may result from the effect of biological mediators found in the tumor microenvironment. Here we show how nitric oxide (NO), a key cellular modulator whose level is elevated in many tumors, affects CSC-like phenotypes of human non-small cell lung carcinoma H292 and H460 cells. Exposure of NO gradually altered the cell morphology toward mesenchymal stem-like shape. NO exposure promoted CSC-like phenotype, indicated by increased expression of known CSC markers, CD133 and ALDH1A1, in the exposed cells. These effects of NO on stemness were reversible after cessation of the NO treatment for 7 days. Furthermore, such effect was reproducible using another NO donor, S-nitroso-Nacetylpenicillamine. Importantly, inhibition of NO by the known NO scavenger 2-(4-carboxy-phenyl)-4,4,5,5 tetramethylimidazoline-1-oxy-3-oxide strongly inhibited CSC-like aggressive cellular behavior and marker expression. Last, we unveiled the underlying mechanism of NO action through the activation of caveolin-1 (Cav-1), which is upregulated by NO and is responsible for the aggressive behavior of the cells, including anoikis resistance, anchorage-independent cell growth, and increased cell migration and invasion. These findings indicate a novel role of NO in CSC regulation and its importance in aggressive cancer behaviors through Cav-1 upregulation.cancer stem cells; nitric oxide; caveolin-1; CD133; ALDH1A1; nonsmall cell lung carcinoma ACCORDING TO THE AMERICAN CANCER SOCIETY 2013 annual cancer statistics, lung cancer remains one of the most common malignancies and is the leading cause of cancer-related deaths worldwide (61). Increasing evidence has indicated the role of cancer stem cells (CSCs) in cancer aggressiveness, chemoresistance, and relapse; they are being considered as the underlying causes of the high mortality rate of cancer (29,47,50,55). The concept of a tumor having a heterogeneous cancer cell population with a subpopulation of cells possessing a high tumorigenic potential and stem-like property was first described in 1997 (5). This subpopulation is commonly known as tumor-initiating cells, tumor-propagating cells, or CSCs and has been identified in many types of cancer (16,23,40,46,56,58,63). CSCs have been suggested as the rationale behind chemo/radioresistance and cancer relapse (3,4,18,39,68) an...

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confidence: 65%

Section: Effect Of Dpta Nonoate On Human Lung Cancer Cell Epithelial-mentioning

confidence: 99%

Nitric oxide induces cancer stem cell-like phenotypes in human lung cancer cells

Yongsanguanchai

Pongrakhananon

Mutirangura

et al. 2015

American Journal of Physiology-Cell Physiology

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“…These results were concordant with those of other studies, in which it was observed that NO suppressed migration and invasion in different tumor cell lines, and the anti-metastasis effects were shown to be associated with the upregulation of N-Myc downstream-regulated gene 1 (NDRG1), inhibition of hypoxia-inducible factor 1 (HIF-1) and impairment of mitochondria (17,26). However, this is in contrast to another study, which demonstrated that long-term (7 or 14 day) treatment with NO significantly increased the migratory action of human lung cancer cells through increased expression of caveolin-1 (Cav-1) and cell division cycle 42 (Cdc42) proteins (27). These conflicting results could be explained by the observation that the final activity of NO in oncology is dependent upon its working microenvironment, including the type of cell exposed to the compound, the redox state of the reaction, as well as the final intracellular concentration and the duration of intracellular exposure to NO (5).…”

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confidence: 76%

Effects of nitric oxide on the biological behavior of HepG2 human hepatocellular carcinoma cells

Zhou

Zhang

2016

Experimental and Therapeutic Medicine

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Abstract. Many studies have found the function of nitric oxide (NO) in cancer as a pro-neoplastic vs. an anti-neoplastic effector, but the role of NO in hepatocellular carcinoma (HCC) remains unclear. The present study aimed to investigate the effects of nitric oxide (NO) on the biological behavior of the human hepatocellular carcinoma cell line HepG2. HepG2 cell was cultured in vitro and treated with or without sodium nitroprusside (SNP), a NO donor. Subsequently, we evaluated the effects of NO in cell proliferation, cell cycle, apoptosis, migration and invasion by MTT assay, flow cytometry, wound healing assay and Matrigel invasion assay. We demonstrate that NO significantly inhibited HepG2 cell proliferation by inducing G 0 /G 1 phase arrest in a dose-dependent manner. In addition, compared to the control group, cells treated with SNP showed obviously higher apoptosis ratios in a dose-dependent manner. Furthermore, we revealed that NO effectively inhibited the ability of migration and invasion of HepG2 cells. Taken together, our results suggested that NO has an important role in the regulation of biological behavior in HepG2 cells and the potential for use in the prevention and treatment of HCC.

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“…O-ASCs can differentiate into adipocytes lineage, promote tumor initiation, growth, vascularization, metastasis, and resistance to chemotherapy in many tumor models (2,10). Recently, we showed that O-ASCs promoted proliferation, migration, chemotherapy, and radiation response of ovarian cancer cells (8).…”

Section: Introductionmentioning

confidence: 99%

“…It has been shown that high levels of NOS activity exist in malignant tissue from gynecologic cancers (18) and higher NOS expressions were correlated to the more advanced stages of breast cancers (19). NO acts in a bimodal manner in cancer research, at low concentrations it increases proliferation, angiogenesis, invasiveness, metastasis, and cytoprotection (10,20,21). However, high concentrations of NO induce extensive DNA damage, oxidative, and nitrosative stress that lead to cytotoxicity and apoptosis of tumor cells (22,23).…”

Section: Introductionmentioning

confidence: 99%

Nitric Oxide Mediates Metabolic Coupling of Omentum-Derived Adipose Stroma to Ovarian and Endometrial Cancer Cells

et al. 2015

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Omental adipose stromal cells (O-ASC) are a multipotent population of mesenchymal stem cells contained in the omentum tissue that promote endometrial and ovarian tumor proliferation, migration, and drug resistance. The mechanistic underpinnings of O-ASCs' role in tumor progression and growth are unclear. Here, we propose a novel nitric oxide (NO)-mediated metabolic coupling between O-ASCs and gynecologic cancer cells in which O-ASCs support NO homeostasis in malignant cells. NO is synthesized endogenously by the conversion of L-arginine into citrulline through nitric oxide synthase (NOS). Through arginine depletion in the media using L-arginase and NOS inhibition in cancer cells using N G -nitro-L-arginine methyl ester (L-NAME), we demonstrate that patientderived O-ASCs increase NO levels in ovarian and endometrial cancer cells and promote proliferation in these cells. O-ASCs and cancer cell cocultures revealed that cancer cells use O-ASCsecreted arginine and in turn secrete citrulline in the microenvironment. Interestingly, citrulline increased adipogenesis potential of the O-ASCs. Furthermore, we found that O-ASCs increased NO synthesis in cancer cells, leading to decrease in mitochondrial respiration in these cells. Our findings suggest that O-ASCs upregulate glycolysis and reduce oxidative stress in cancer cells by increasing NO levels through paracrine metabolite secretion. Significantly, we found that O-ASCmediated chemoresistance in cancer cells can be deregulated by altering NO homeostasis. A combined approach of targeting secreted arginine through L-arginase, along with targeting microenvironment-secreted factors using L-NAME, may be a viable therapeutic approach for targeting ovarian and endometrial cancers. Cancer Res; 75(2); 456-71. Ó2014 AACR.

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Long-Term Nitric Oxide Exposure Enhances Lung Cancer Cell Migration

Cited by 37 publications

References 35 publications

Nitric oxide induces cancer stem cell-like phenotypes in human lung cancer cells

Nitric oxide induces cancer stem cell-like phenotypes in human lung cancer cells

Effects of nitric oxide on the biological behavior of HepG2 human hepatocellular carcinoma cells

Nitric Oxide Mediates Metabolic Coupling of Omentum-Derived Adipose Stroma to Ovarian and Endometrial Cancer Cells

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