Article
Hypoxia inducible transcription factor HIF-2a interferes with cisplatin induced cell death in adenocarcinoma cells in vitro
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Published: | March 20, 2006 |
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Hypoxia is known to affect tumor progression and drug resistance. This study investigated the possible significance of hypoxia-inducible factors (HIFs) in hypoxic adenocarcinoma (A549) cells, exposed to cisplatin chemotherapy. In normoxic A549 cells, cisplatin (0.1µg/µl) reduced cell survival to 32,3% ± 5,1%, as assessed by MTT assay. In hypoxia, cisplatin exerted only a minor MTT-decrease of 9,16% ± 6%. For analyzes of interaction of cisplatin with hypoxia-induced signal transduction we measured activation of the hypoxia responsive element (HRE), the binding domain of the hypoxia transcription factors (HIF-1a and HIF-2a). Cisplatin demonstrated activation of HRE both in normoxia and hypoxia. Vice versa, we analyzed the effect of HIF inhibition on cisplatin toxicity. Specific inhibition of HIF-2a by synthetic siRNA significantly increased the toxicity of cisplatin, whereas suppression of HIF-1a by siRNA or a random siRNA control had no effect. Thus, we conclude that hypoxia suppresses the response to cisplatin in A549 cells through activation of HIF-2. Targeting HIF-2 by RNA interference may represent a new strategy to improve the response to cisplatin in hypoxic tumor cells.