Cells Silenced for SDHB Expression Display Characteristic Features of the Tumor Phenotype
| العنوان: | Cells Silenced for SDHB Expression Display Characteristic Features of the Tumor Phenotype |
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| المؤلفون: | Nadezda Apostolova, Manuel de la Mata, Francisco Luna Crespo, Ana M. Cervera, Kenneth J. McCreath |
| المصدر: | Cancer Research. 68:4058-4067 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2008. |
| سنة النشر: | 2008 |
| مصطلحات موضوعية: | Cancer Research, Small interfering RNA, SDHB, Citric Acid Cycle, Biology, Cell Line, Tumor, Neoplasms, Humans, Gene silencing, Gene Silencing, Phosphorylation, Transcription factor, DNA Primers, Oligonucleotide Array Sequence Analysis, Base Sequence, Reverse Transcriptase Polymerase Chain Reaction, Microarray analysis techniques, Kinase, Molecular biology, Cell biology, Succinate Dehydrogenase, Oncology, Mutation, SDHD, Hypoxia Pathway, Reactive Oxygen Species |
| الوصف: | Recently, enzymes of the tricarboxylic acid (TCA) cycle have emerged as novel tumor suppressors. In particular, mutations in the nuclear-encoded subunits of succinate dehydrogenase (SDHB, SDHC, and SDHD) cause paragangliomas and pheochromocytomas. Although the mechanism(s) by which disruption of mitochondrial metabolism leads to neoplasia is largely unknown, increasing evidence points to an activation of pseudohypoxia. In this study, we have shown that silencing of SDHB using DNA-based small interfering RNA resulted in major impairments in cellular proliferation, respiration, and a corresponding shift to glycolysis. The levels of reactive oxygen species, however, were unchanged. As expected, hypoxia-inducible factor-1α (HIF-1α) and HIF-2α were up-regulated in chronically silenced cells, suggesting that a pseudohypoxic state was attained. In addition, the c-Jun amino-terminal kinase and p38 kinase stress signaling proteins were hyperphosphorylated in SDHB-silenced cells. Microarray analysis showed that >400 genes were influenced (6-fold or more up-regulation or down-regulation) by silencing of SDHB, confirming the importance of the TCA cycle in cellular metabolism. Examples of dysregulated genes included those involved in proliferation, adhesion, and the hypoxia pathway. Of interest, SDHB-silenced cells had a greater capacity to adhere to extracellular matrix components, including fibronectin and laminin, than control cells, thus suggesting a possible mechanism of tumor initiation. Although transient silencing of the HIF-1α transcription factor in SDHB-silenced cells had little effect on the expression of a subset of up-regulated genes, it partially reversed the adhesion phenotype to fibronectin, pointing to a potentially important role for HIF-1 in this process. [Cancer Res 2008;68(11):4058–67] |
| تدمد: | 1538-7445 0008-5472 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7c3bb5aaa49f8ea94520e0ca1f2bf117 https://doi.org/10.1158/0008-5472.can-07-5580 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....7c3bb5aaa49f8ea94520e0ca1f2bf117 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15387445 00085472 |
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