PT - JOURNAL ARTICLE AU - Christoph Wohlkoenig AU - Katharina Leithner AU - Andelko Hrzenjak AU - Andrea Olschewski AU - Horst Olschewski TI - Possible role of nuclear receptor nr4a1 in hypoxia-induced cisplatin resistance DP - 2013 Sep 01 TA - European Respiratory Journal PG - P3109 VI - 42 IP - Suppl 57 4099 - http://erj.ersjournals.com/content/42/Suppl_57/P3109.short 4100 - http://erj.ersjournals.com/content/42/Suppl_57/P3109.full SO - Eur Respir J2013 Sep 01; 42 AB - Background:Many apoptosis-inducing agents induce cell-death by activating the orphan nuclear receptor nr4a1. Upon this activation nr4a1 is shifted from nucleus to mitochondria, where it is changing the conformation of the anti-apoptotic protein bcl-2 to a pro-apoptotic protein. However, in solid tumours in vivo hypoxic conditions prevail and these conditions add to chemotherapy resistance. It is still unknown whether apoptosis induction through nr4a1-mediated functional changes of bcl-2 is relevant under hypoxic conditions.Methods:A549 cells were treated with cisplatin under normoxia and hypoxia for predefined time periods. Cell proteins were harvested and separated into nuclear, cytoplasmic and mitochondrial fraction using commercial kits. Thereafter western blots were performed to assess the expression of nr4a1.Results:We found a down regulation of nr4a1 in the cytoplasmic fraction and an up regulation in the mitochondrial fraction following cisplatin treatment under normoxia. However, the same treatment under hypoxic conditions (1% O2) did not lead to an up regulation of mitochondrial nr4a1 (Fig.). Interestingly, under both conditions nuclear content did not change.Conclusion:We conclude that mitochondrial induction of apoptosis through nr4a1 may be suppressed by hypoxia and might represent an additional mechanism of hypoxia-induced cisplatin resistance.