Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / metabolism
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Antineoplastic Agents, Phytogenic / pharmacology*
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Apoptosis / drug effects*
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Cell Hypoxia
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Cell Proliferation / drug effects
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Drug Resistance, Neoplasm*
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Etoposide / pharmacology*
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GTP Phosphohydrolases / genetics
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GTP Phosphohydrolases / metabolism
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HeLa Cells
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Membrane Potential, Mitochondrial / drug effects
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Membrane Transport Proteins / genetics
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Membrane Transport Proteins / metabolism
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Mitochondria / metabolism
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Mitochondria / pathology*
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Mitochondrial Membrane Transport Proteins
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / metabolism
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Mitochondrial Swelling*
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Neoplasms / genetics
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Neoplasms / metabolism
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Neoplasms / pathology*
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Phenotype
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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RNA Interference
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Staurosporine / pharmacology*
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Time Factors
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Transfection
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
Substances
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Antineoplastic Agents, Phytogenic
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BNIP3 protein, human
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BNIP3L protein, human
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Membrane Proteins
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Membrane Transport Proteins
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Mitochondrial Membrane Transport Proteins
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Mitochondrial Proteins
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Proto-Oncogene Proteins
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Tumor Suppressor Proteins
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Etoposide
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Adenosine Triphosphate
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GTP Phosphohydrolases
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Mfn1 protein, human
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Staurosporine