Document Detail

Hypoxic enlarged mitochondria protect cancer cells from apoptotic stimuli.
MedLine Citation:
PMID:  19957303     Owner:  NLM     Status:  MEDLINE    
It is well established that cells exposed to the limiting oxygen microenvironment (hypoxia) of tumors acquire resistance to chemotherapy, through mechanisms not fully understood. We noted that a large number of cell lines showed protection from apoptotic stimuli, staurosporine, or etoposide, when exposed to long-term hypoxia (72 h). In addition, these cells had unusual enlarged mitochondria that were induced in a HIF-1-dependent manner. Enlarged mitochondria were functional as they conserved their transmembrane potential and ATP production. Here we reveal that mitochondria of hypoxia-induced chemotherapy-resistant cells undergo a HIF-1-dependent and mitofusin-1-mediated change in morphology from a tubular network to an enlarged phenotype. An imbalance in mitochondrial fusion/fission occurs since silencing of not only the mitochondrial fusion protein mitofusin 1 but also BNIP3 and BNIP3L, two mitochondrial HIF-targeted genes, reestablished a tubular morphology. Hypoxic cells were insensitive to staurosporine- and etoposide-induced cell death, but the silencing of mitofusin, BNIP3, and BNIP3L restored sensitivity. Our results demonstrate that some cancer cells have developed yet another way to evade apoptosis in hypoxia, by inducing mitochondrial fusion and targeting BNIP3 and BNIP3L to mitochondrial membranes, thereby giving these cells a selective growth advantage.
Johanna Chiche; Matthieu Rouleau; Pierre Gounon; M Christiane Brahimi-Horn; Jacques Pouysségur; Nathalie M Mazure
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of cellular physiology     Volume:  222     ISSN:  1097-4652     ISO Abbreviation:  J. Cell. Physiol.     Publication Date:  2010 Mar 
Date Detail:
Created Date:  2010-01-04     Completed Date:  2010-01-19     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0050222     Medline TA:  J Cell Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  648-57     Citation Subset:  IM    
Institute of Developmental Biology and Cancer Research, CNRS-UMR 6543, Centre Antoine Lacassagne, University of Nice, 06189 Nice, France.
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MeSH Terms
Adenosine Triphosphate / metabolism
Antineoplastic Agents, Phytogenic / pharmacology*
Apoptosis / drug effects*
Cell Hypoxia
Cell Proliferation / drug effects
Drug Resistance, Neoplasm*
Etoposide / pharmacology*
GTP Phosphohydrolases / genetics,  metabolism
Hela Cells
Hypoxia-Inducible Factor 1, alpha Subunit / genetics,  metabolism
Membrane Potential, Mitochondrial / drug effects
Membrane Proteins / genetics,  metabolism
Membrane Transport Proteins / genetics,  metabolism
Mitochondria / metabolism,  pathology*
Mitochondrial Proteins / genetics,  metabolism
Mitochondrial Swelling*
Neoplasms / genetics,  metabolism,  pathology*
Proto-Oncogene Proteins / genetics,  metabolism
RNA Interference
Staurosporine / pharmacology*
Time Factors
Tumor Suppressor Proteins / genetics,  metabolism
Reg. No./Substance:
0/Antineoplastic Agents, Phytogenic; 0/BNIP3 protein, human; 0/BNIP3L protein, human; 0/HIF1A protein, human; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/Membrane Proteins; 0/Membrane Transport Proteins; 0/Mitochondrial Proteins; 0/Proto-Oncogene Proteins; 0/Tumor Suppressor Proteins; 33419-42-0/Etoposide; 56-65-5/Adenosine Triphosphate; 62996-74-1/Staurosporine; EC 3.6.1.-/GTP Phosphohydrolases; EC 3.6.5.-/Mfn1 protein, human

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