Nitric Oxide Synthase-2-Derived Nitric Oxide Drives Multiple Pathways of Breast Cancer Progression

Basudhar, Debashree; Somasundaram, Veena; Oliveira, Gustavo H. C.; Kesarwala, Aparna H.; Heinecke, Julie L.; Cheng, Robert; Glynn, Sharon A.; Ambs, Stefan; Wink, David A.; Ridnour, Lisa A.

doi:10.1089/ars.2016.6813

Cited by 68 publications

(60 citation statements)

References 163 publications

(228 reference statements)

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“…Through functional enrichment, we identified that NO can induce multiple molecular pathways such as protein kinase activity, estrogen receptor activity, BMP receptor binding, ligand-gated ion channel activity, or phosphatidylinositol 3-phosphate binding. Consistent with our results, many studies have demonstrated the relationship between NO and estrogen receptor signaling in several biological processes including osteogenic development [44][45][46]. Moreover, BMP signaling-induced NO production stimulated bone calcification in zebrafish [47].…”

Section: Cellular Physiology and Biochemistry Cellular Physiology Andsupporting

confidence: 92%

Osteogenic Effect of Inducible Nitric Oxide Synthase (iNOS)-Loaded Mineralized Nanoparticles on Embryonic Stem Cells

Lee¹,

Lee²,

Lee³

et al. 2018

Cell Physiol Biochem

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Background/Aims: This study investigated the effect of inducible nitric oxide synthase-loaded mineralized nanoparticles (iNOS-MNPs) on the osteogenic differentiation of mouse embryonic stem cells (ESCs). Methods: We prepared iNOS-MNPs using an anionic block copolymer template-mediated calcium carbonate (CaCO₃) mineralization process in the presence of iNOS. iNOS-MNPs were spherical and had a narrow size distribution. iNOS was stably loaded within MNPs without denaturation. In order to confirm the successful introduction of iNOS-MNPs into the cytosol of ESCs, intracellular levels of nitric oxide (NO) was determined with a fluorometric analysis. A NO effector molecule, cyclic guanosine 3’,5’ monophosphate (cGMP) was also quantified with a competitive enzyme immunoassay. Cell viability in response to iNOS-MNP treatment was determined using the cell counting kit-8 (CCK-8) assay. Alkaline phosphatase (ALP) activity assay, intracellular calcium quantification assay, and Alizarin red S staining for matrix mineralization were performed to investigate osteogenic differentiation of ESCs. The protein levels of Runt-related transcription factor 2 (RUNX2), osteocalcin (OCN), and osterix (OSX) as osteogenic-related factors were also assessed by immunofluorescence staining and Western blot analysis. The complex pathways associated with iNOS-MNP-derived osteogenic differentiation of ESCs were evaluated by network-based analysis. Results: Cells with iNOS-MNPs displayed a significant increase in NO and cGMP concentration compared with the control group. When cells were exposed to iNOS-MNPs, there were no adverse effects on cell viability. Importantly, iNOS-MNP uptake promoted the osteogenic differentiation of ESCs. Using transcriptome profiling, we obtained 1,836 differentially-induced genes and performed functional enrichment analysis with ClueGO and KEGG. These analyses identified significantly enriched and interconnected molecular pathways such as protein kinase activity, estrogen receptor activity, bone morphogenetic protein (BMP) receptor binding, ligand-gated ion channel activity, and phosphatidylinositol 3-phosphate binding. Conclusion: These findings suggest that iNOS-MNPs can induce osteogenic differentiation in ESCs by integrating complex signaling pathways.

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Section: Cellular Physiology and Biochemistry Cellular Physiology Andsupporting

confidence: 92%

Osteogenic Effect of Inducible Nitric Oxide Synthase (iNOS)-Loaded Mineralized Nanoparticles on Embryonic Stem Cells

Lee¹,

Lee²,

Lee³

et al. 2018

Cell Physiol Biochem

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“…On the other hand, a large body of experimental and clinical data suggests a promoting role of NO in tumor progression and metastasis. Expression of iNOS has been reported in malignancies of the breast [77, 151, 152], prostate [153], lung [154], brain [155] and colon [156, 157]. It appears that, low concentrations of NO of less than 100 nM prevents certain cell types from apoptosis, and thereby favor tumorigenesis and progression [158, 159].…”

Section: The Yin – Yang Of No and H2s In Carcinogenesismentioning

confidence: 99%

The dichotomous role of H2S in cancer cell biology? Déjà vu all over again

Kashfi

2018

Biochemical Pharmacology

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Nitric oxide (NO) a gaseous free radical is one of the ten smallest molecules found in nature, while hydrogen sulfide (HS) is a gas that bears the pungent smell of rotten eggs. Both are toxic yet they are gasotransmitters of physiological relevance. There appears to be an uncanny resemblance between the general actions of these two gasotransmitters in health and disease. The role of NO and HS in cancer has been quite perplexing, as both tumor promotion and inflammatory activities as well as anti-tumor and antiinflammatory properties have been described. These paradoxes have been explained for both gasotransmitters in terms of each having a dual or biphasic effect that is dependent on the local flux of each gas. In this review/commentary, I have discussed the major roles of NO and HS in carcinogenesis, evaluating their dual nature, focusing on the enzymes that contribute to this paradox and evaluate the pros and cons of inhibiting or inducing each of these enzymes.

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“…NO has multiple facets and can have relevant roles in several pathological conditions, such as cardiovascular, pulmonary, neurodegenerative, infectious diseases and cancer (3). Specifically in cancer, NO is considered to have dual effects because it can be pro-tumorigenesis, but at the same time, depending on the circumstances it can also have anti-tumorigenesis effects, such as inducing apoptosis, reducing invasion and metastasis and supressing DNA synthesis (4, 5) (6) (7). When NO acts with a tumor promoting role, several mechanisms have been involved, including: genotoxic mechanisms, anti-apoptotic effects, induction of angiogenesis, reduction of host immune response against tumor or promoting metastasis (5).…”

Section: Introductionmentioning

confidence: 99%

NO control of mitochondrial function in normal and transformed cells

Tengan¹,

Moraes²

2017

Biochimica et Biophysica Acta (BBA) - Bioenergetics

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Nitric oxide (NO) is a signaling molecule with multiple facets and involved in numerous pathological process, including cancer. Among the different pathways where NO has a functionally relevant participation, is the control of mitochondrial respiration and biogenesis. NO is able to inhibit the electron transport chain, mainly at Complex IV, regulating oxygen consumption and ATP generation, but at the same time, can also induce increase in reactive oxygen and nitrogen species. The presence of reactive species can induce oxidative damage or participate in redox signaling. In this review, we discuss how NO affects mitochondrial respiration and mitochondrial biogenesis, and how it influences the development of mitochondrial deficiency and cancer.

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Nitric Oxide Synthase-2-Derived Nitric Oxide Drives Multiple Pathways of Breast Cancer Progression

Cited by 68 publications

References 163 publications

Osteogenic Effect of Inducible Nitric Oxide Synthase (iNOS)-Loaded Mineralized Nanoparticles on Embryonic Stem Cells

Osteogenic Effect of Inducible Nitric Oxide Synthase (iNOS)-Loaded Mineralized Nanoparticles on Embryonic Stem Cells

The dichotomous role of H2S in cancer cell biology? Déjà vu all over again

NO control of mitochondrial function in normal and transformed cells

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