Document Detail


Role of hypoxia and autophagy in MDA-MB-231 invasiveness.
MedLine Citation:
PMID:  20112292     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Manuela Indelicato; Bruna Pucci; Luana Schito; Valentina Reali; Michele Aventaggiato; Maria C Mazzarino; Franca Stivala; Massimo Fini; Matteo A Russo; Marco Tafani
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of cellular physiology     Volume:  223     ISSN:  1097-4652     ISO Abbreviation:  J. Cell. Physiol.     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-03-01     Completed Date:  2010-05-06     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0050222     Medline TA:  J Cell Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  359-68     Citation Subset:  IM    
Affiliation:
Department of Cellular and Molecular Pathology, IRCCS San Raffaele Pisana, 00163 Rome, Italy. manuela.indelicato@sanraffaele.it
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MeSH Terms
Descriptor/Qualifier:
Adenine / 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:
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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