Hypoxia-inducible-factor 2 alpha mediates cisplatin resistance in the lung adenocarcinoma cell line A549

• Published in: Journal of clinical oncology Vol. 25; no. 18_suppl; p. 10573
• Main Authors: Rose, F., Eul, B., Kwapiszewska, G., Marsh, L., Kamlah, F., Seeger, W., Grimminger, F., Lohmeyer, J., Haenze, J.
• Format: Journal Article
• Language: English
• Published: 20.06.2007
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/jco.2007.25.18_suppl.10573

Abstract only 10573 Background: Hypoxia in solid tumors is associated with cancer progression, metastasis and resistance to chemotherapy. The hypoxia inducible factors (HIF-1a and HIF-2a) are key players in the response to hypoxia affecting angiogenesis, proliferation and apoptosis. Here we investigated the role of HIF-1a and HIF-2a in cellular resistance to cisplatin in non small lung cancer cells (A549). Results: Hypoxia reduced the efficiency of cisplatin treatment on A549 cells via enhancement of drug efflux activity. In addition, hypoxia induced the hypoxia-responsive-element (HRE) reporter gene assay, demonstrating the transcriptional activity of HIF-1a and HIF-2a. Administration of cisplatin further increased the reporter activity under both normoxic and hypoxic conditions. This correlated with the induction of HIF-2a protein expression upon cisplatin treatment in normoxia and hypoxia, whereas HIF-1a was suppressed. Additionally, cisplatin induced nuclear accumulation of HIF-2a. Suppression of HIF-2a by RNA interference potentiated the sensitivity to cisplatin treatment in hypoxic A549 cells. In vivo growth delay assay gave analogues results for subcutaneous A549 tumors treated with cisplatin and suppression of HIF-2a. In comparison, other cytostatic drugs such as doxorubicin and gemcitabine differed with respect to HIF signalling. Doxorubicin induced both HIF-1a and HIF- 2a. Cellular sensitivity to doxorubicin was increased via suppression of HIF-1a and HIF-2a. Gemcitabine appeared to act independent of HIF. The underlying mechanism of hypoxia-induced resistance was due to increased mRNA expression of drug resistance proteins such as MDR1, MRP1 and LRP. These were found to be HIF-2a but not HIF-1a dependent. Conclusion: This data identified HIF-2a as a key player in the hypoxia induced cisplatin resistance and show on the molecular level that HIF-2a is a credible target for therapeutic strategies. No significant financial relationships to disclose.