Targeting PI3K/Akt represses Hypoxia inducible factor-1α activation and sensitizes Rhabdomyosarcoma and Ewing’s sarcoma cells for apoptosis

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• 作者：Mehtap Kilic-Eren (1)
  Tulin Boylu (2)
  Vedrana Tabor (3)
  
• 关键词：PI3K/Akt ; Hypoxia ; HIF ; 1α ; Apoptosis ; Rhabdomyosarcoma ; Ewing’s sarcoma
• 刊名：Cancer Cell International
• 出版年：2013
• 出版时间：December 2013
• 年：2013
• 卷：13
• 期：1
• 全文大小：462KB
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• 作者单位：Mehtap Kilic-Eren (1)
  Tulin Boylu (2)
  Vedrana Tabor (3)
  
  1. Department of Medical Biology, Faculty of Medicine, Adnan Menderes University, Aydin, Turkey
  2. Department of Histology and Embryology, Faculty of Medicine, Adnan Menderes University, Aydin, Turkey
  3. Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
  

文摘

Background Hypoxia inducible factor-1 α (HIF-1α) has been identified as an important novel target in apoptosis resistance of pediatric tumors such as Rhabdomyosarcoma (RMS) and Ewing’s sarcoma (ES). Evidence suggests that PI3K/Akt signaling plays a role in regulation of HIF-1α activation as well as apoptosis resistance in various adult tumors. However the relevance of PI3K/Akt signaling in HIF-1bα activation and apoptosis resistance in childhood tumors has not been addressed yet. Thus, this study was to investigate whether PI3K/Akt signaling is involved in hypoxia induced activation of HIF-1α as well as in resistance to hypoxia-induced apoptosis in childhood tumors such as RMS and ES. Methods Constitutive activation of PI3K/Akt signaling was analyzed by Western blotting. Hypoxic activation of HIF-1α was determined by Western Blot analysis and electrophoretic mobility shift assay. Apoptosis was determined by flow cytometric analysis of the propidium iodine stained nuclei of cells treated with PI3K inhibitor LY294002 in combination with either TNF-related apoptosis-inducing ligand (TRAIL) or doxorubicin. Results This study demonstrated that PI3K/Akt signaling was constitutively activated in RMS and ES cell lines, A204 and A673, respectively. Targeting PI3K/Akt signaling by the inhibitor LY294002 (30?μM) significantly decreased the protein expression as well as DNA binding activity of HIF-1α and restored the apoptosis-inducing ability of cells in hypoxia Additionally, pretreatment with LY294002 sensitized A204 and A673 cells to TRAIL or doxorubicin induced apoptosis under hypoxia. Conclusion These results suggest that the constitutively active PI3K/Akt signaling contributes to hypoxic activation of HIF-1α as well as HIF1α-mediated apoptosis resistance in RMS and ES cells under hypoxia.