Array-based comparative gene expression analysis of tumor cells with increased apoptosis resistance after hypoxic selection

• Published in: Oncogene Vol. 24; no. 38; pp. 5914 - 5922
• Main Authors: WEINMANN, Martin, BELKA, Claus, GÜNER, Dilek, GOECKE, Barbara, MÜLLER, Ilka, BAMBERG, Michael, JENDROSSEK, Verena
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 01.09.2005; Nature Publishing Group
• Subjects: Ageing, cell death; Apoptosis; Apoptosis - physiology; Biological and medical sciences; Cell death; Cell Hypoxia - genetics; Cell Line, Tumor; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; DNA microarrays; Fundamental and applied biological sciences. Psychology; Gene Expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Hypoxia; Lung Neoplasms - genetics; Mitochondria; Molecular and cellular biology; Oligonucleotide Array Sequence Analysis; Signal transduction; Tumor cells; Oxygen; apoptosis resistance; microarray analysis; Selection; Gene expression; Microarray; Carcinogenesis; Resistance; Mitochondria; gene expression pattern; Analysis; Hypoxia; Tumor cell; Apoptosis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1208748

Tumor hypoxia is an adverse prognostic factor. In a recent study, we could demonstrate that cyclic hypoxia selects for hypoxia-tolerant tumor cells, which are cross-resistant to other stimuli of mitochondrial death pathways. In contrast, sensitivity of the cells to death-receptor ligands was mainly not affected. The aim of the present study was to further elucidate cellular changes induced by cyclic hypoxia and to identify alterations in gene expression pattern upon hypoxic selection by means of DNA-microarray analysis. Our data reveal that cyclic hypoxia resulted in the selection of cells with resistance to doxorubicine and radiation. Furthermore, hypoxic selection was accompanied by constitutive changes of the gene expression pattern with downregulation of 156 and upregulation of 82 genes. Most of the differentially regulated genes were involved in cellular responses to hypoxia and reoxygenation. While many of the genes that were downregulated upon hypoxic selection represent genes that are usually upregulated by acute hypoxia, the genes that were upregulated represent genes that are involved in stress resistance and anti-apoptotic signalling. Most importantly, hypoxic selection was not associated with changes of single apoptosis relevant genes, but with alterations in gene expression levels of a wide variety of genes indicating a more complex adaptation process.