| Role of hypoxia and autophagy in MDA-MB-231 invasiveness. | |
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MedLine Citation:
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PMID: 20112292 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Survival strategies adopted by tumor cells in response to a hypoxic stress include activation of hypoxia-inducible factor 1 (HIF-1) and autophagy. However, the importance and the function of each molecular response is not well defined. In the present study, we investigated invasiveness, migration, matrix metalloproteinases (MMPs) activity, and cell survival of MDA-MB-231 cells under normoxia, hypoxia, and hypoxia/reoxygenation (H/R). Moreover, to assess the importance of hypoxia and autophagy on the parameters studied, cells were either left untreated or treated with Chetomin (a selective inhibitor of HIF-1alpha) or trifluoperazine (TFP, an activator of autophagy). We found that hypoxia and H/R stimulated invasiveness and migration of MDA-MB-231 cells with an increased MMP-2 activity. Chetomin and TFP differently regulated the cellular behavior under the oxygenation conditions studied. In fact, Chetomin was most effective in inhibiting cell invasion, MMPs activity, and cell survival under hypoxia but not normoxia or H/R. By contrast, TFP inhibition of cell invasion, migration, and cell survival was independent from oxygenation conditions. TFP-induced autophagy was inhibited by light chain protein 3 (LC3) silencing or 3-methyladenine (3MA) treatment. In fact, LC3-silenced cells were able to invade in the presence of TFP without any GATE16 processing and p62 degradation. Immunofluorescence assay showed that LC3 silencing inhibited TFP-induced autophagosome formation. However, we also showed that both TPF treatment and LC3 silencing caused cytoskeleton impairments suggesting a possible interaction between LC3 and cytoskeleton components. In conclusion, our study shows that hypoxia and autophagy by acting on common (HIF-1alpha) or separate (MMPs, cytoskeleton) targets differently regulate cell invasion, MMPs activity, and survival. |
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Authors:
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Manuela Indelicato; Bruna Pucci; Luana Schito; Valentina Reali; Michele Aventaggiato; Maria C Mazzarino; Franca Stivala; Massimo Fini; Matteo A Russo; Marco Tafani |
Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Journal of cellular physiology Volume: 223 ISSN: 1097-4652 ISO Abbreviation: J. Cell. Physiol. Publication Date: 2010 May |
Date Detail:
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Created Date: 2010-03-01 Completed Date: 2010-05-06 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0050222 Medline TA: J Cell Physiol Country: United States |
Other Details:
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Languages: eng Pagination: 359-68 Citation Subset: IM |
Affiliation:
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Department of Cellular and Molecular Pathology, IRCCS San Raffaele Pisana, 00163 Rome, Italy. manuela.indelicato@sanraffaele.it |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adenine
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analogs & derivatives,
pharmacology Autophagy / drug effects, physiology* Cell Hypoxia / physiology Cell Line, Tumor Cell Migration Assays Cell Movement / physiology Cell Survival / physiology Cytoskeleton / metabolism Disulfides / pharmacology Dopamine Antagonists / pharmacology Extracellular Matrix / enzymology Female Humans Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors, metabolism Indole Alkaloids / pharmacology Matrix Metalloproteinase 2 / metabolism Matrix Metalloproteinases / metabolism Microtubule-Associated Proteins / genetics Neoplasm Invasiveness / physiopathology* Neoplasms / metabolism*, physiopathology* Oxygen Consumption / physiology Phagosomes / drug effects, metabolism RNA Interference Trifluoperazine / pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Disulfides; 0/Dopamine Antagonists; 0/HIF1A protein, human; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/Indole Alkaloids; 0/Microtubule-Associated Proteins; 0/light chain 3, human; 117-89-5/Trifluoperazine; 1403-36-7/chetomin; 5142-23-4/3-methyladenine; 73-24-5/Adenine; EC 3.4.24.-/Matrix Metalloproteinases; EC 3.4.24.24/Matrix Metalloproteinase 2 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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