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Cyclic exposure to hypoxia and reoxygenation selects for tumor cells with defects in mitochondrial apoptotic pathways
Author(s) -
Weinmann Martin,
Jendrossek Verena,
Güner Dilek,
Goecke Barbara,
Belka Claus
Publication year - 2004
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-1918fje
Subject(s) - apoptosis , hypoxia (environmental) , microbiology and biotechnology , mitochondrion , biology , programmed cell death , signal transduction , intracellular , cancer research , chemistry , oxygen , biochemistry , organic chemistry
The negative influence of hypoxia on the outcome of malignant tumors may be caused by direct oxygen effects, and potentially, the selection of resistant tumor cells under repetitive hypoxia. To evaluate whether cyclic hypoxia selects for resistant cells and to analyze the underlying mechanisms, the influence of cyclic hypoxia on intracellular death pathways was determined in tumor cells. It could be demonstrated that cyclic hypoxia selects for cells with increased resistance against hypoxia‐induced apoptosis. These cells exhibited a cross‐resistance against paradigmatic triggers of mitochondrial apoptotic pathways (ionizing radiation/etoposide). In contrast, TRAIL‐receptor mediated apoptosis remained unaffected. Thus, cyclic hypoxia selects for cells with defects of the mitochondrial rather than receptor‐mediated pathways. Selection of p53‐defective cells has been described as a consequence of cyclic hypoxia; therefore, we evaluated the impact of hypoxic selection on activation of p21 and downstream mediators of p53‐dependent apoptosis. p53 function and protein levels of key mediators of mitochondrial apoptosis remained unaffected by hypoxic selection. However, radiation‐induced conformational changes of Bax were reduced after cyclic hypoxia. In summary, it could be demonstrated that hypoxic stress confers a selection pressure on mitochondrial apoptotic pathways and, consecutively, to an increased resistance toward mitochondrial death triggers.