Nitric oxide synthase and breast cancer: role of TIMP-1 in NO-mediated Akt activation

Autor: Harry B. Hines, Lisa A. Ridnour, Tiffany H. Dorsey, Kimberly M. Barasch, Robert Y.S. Cheng, Ernst E. Brueggemann, Stefan Ambs, David A. Wink, Christopher H. Switzer, Michael M. Lizardo, Dong H. Lee, Harris G. Yfantis, Alisha N. Windhausen, Chand Khanna, Sharon A. Glynn, Julie L. Heinecke
Jazyk: angličtina
Rok vydání: 2012
Předmět:
CD36 Antigens
Colorectal cancer
lcsh:Medicine
Signal Initiation
Molecular Cell Biology
Breast Tumors
Phosphorylation
lcsh:Science
Microscopy
Confocal
Multidisciplinary
Chemistry
Mechanisms of Signal Transduction
Obstetrics and Gynecology
Immunohistochemistry
Signaling Cascades
Gene Expression Regulation
Neoplastic
Treatment Outcome
Oncology
Medicine
Female
Signal transduction
Signal Transduction
Research Article
Feedback Regulation
Breast Neoplasms
Phosphoinositide Signal Transduction
Nitric Oxide
Signaling Pathways
Gene Expression Regulation
Enzymologic
Cell surface receptor
Breast Cancer
Akt Signaling Cascade
medicine
Humans
Biology
Protein kinase B
PI3K/AKT/mTOR pathway
Tissue Inhibitor of Metalloproteinase-1
lcsh:R
Cancers and Neoplasms
Cancer
Oligonucleotides
Antisense
medicine.disease
Molecular biology
Enzyme Activation
Cancer cell
Cancer research
lcsh:Q
Nitric Oxide Synthase
Proto-Oncogene Proteins c-akt
Zdroj: PLoS ONE, Vol 7, Iss 9, p e44081 (2012)
PLoS ONE
ISSN: 1932-6203
Popis: Prediction of therapeutic response and cancer patient survival can be improved by the identification of molecular markers including tumor Akt status. A direct correlation between NOS2 expression and elevated Akt phosphorylation status has been observed in breast tumors. Tissue inhibitor matrix metalloproteinase-1 (TIMP-1) has been proposed to exert oncogenic properties through CD63 cell surface receptor pathway initiation of pro-survival PI3k/Akt signaling. We employed immunohistochemistry to examine the influence of TIMP-1 on the functional relationship between NOS2 and phosphorylated Akt in breast tumors and found that NOS2-associated Akt phosphorylation was significantly increased in tumors expressing high TIMP-1, indicating that TIMP-1 may further enhance NO-induced Akt pathway activation. Moreover, TIMP-1 silencing by antisense technology blocked NO-induced PI3k/Akt/BAD phosphorylation in cultured MDA-MB-231 human breast cancer cells. TIMP-1 protein nitration and TIMP-1/CD63 co-immunoprecipitation was observed at NO concentrations that induced PI3k/Akt/BAD pro-survival signaling. In the survival analysis, elevated tumor TIMP-1 predicted poor patient survival. This association appears to be mainly restricted to tumors with high NOS2 protein. In contrast, TIMP-1 did not predict poor survival in patient tumors with low NOS2 expression. In summary, our findings suggest that tumors with high TIMP-1 and NOS2 behave more aggressively by mechanisms that favor Akt pathway activation.
Databáze: OpenAIRE
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