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Role of hypoxia inducible factor-1 alpha in modulation of apoptosis resistance.
- Source :
-
Oncogene [Oncogene] 2007 Mar 29; Vol. 26 (14), pp. 2027-38. Date of Electronic Publication: 2006 Oct 16. - Publication Year :
- 2007
-
Abstract
- Hypoxia inducible factor-1 (HIF-1) is the major transcription factor and key regulator of adoptive responses to hypoxia. Although it usually promotes tumor cell survival under hypoxia, it has also been implied to trigger apoptosis. Although the impact of hypoxia has been extensively studied in many adult solid tumors, its role in most childhood tumors, for example, in rhabdomyosarcoma (RMS) or Ewing sarcoma (ES), has not yet been addressed. Here, we report that hypoxia protects A204 RMS and A673 ES cells against anticancer drug- or tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis and that Hif-1alpha plays a key role in conferring apoptosis resistance under hypoxia. Although a functional HIF-1 pathway and proapoptotic proteins such as p53 and Bcl-2/E1B 19 kDa interacting protein 3 were activated under hypoxia in both A204 RMS and A673 ES cells, these cells remained refractory to apoptosis. Concomitant analysis of antiapoptotic proteins revealed that hypoxia induced expression of Bcl-2 and inhibitor of apoptosis proteins (IAP)-2 as well as proteins associated with anaerobic metabolism such as the glucose transporter protein GLUT-1 and the glycolytic enzyme Aldolase A. Specific downregulation of Hif-1alpha by RNA interference significantly enhanced apoptosis under hypoxia by preventing the hypoxia-mediated increase in GLUT-1 expression without altering expression levels of the antiapoptotic proteins Bcl-2 or cIAP-2. Moreover, glucose deprivation-induced apoptosis of A204 RMS and A673 ES cells was inhibited under hypoxic conditions in a Hif-1alpha-dependent manner. As GLUT-1 was induced via Hif-1alpha under hypoxia in A204 RMS and A673 ES, these findings suggest that the Hif-1alpha-mediated increase in glucose uptake plays an important role in conferring apoptosis resistance. Thus, hypoxia-inducible genes may represent novel targets for therapeutic intervention in some pediatric tumors, which warrants further investigation.
- Subjects :
- Apoptosis Regulatory Proteins genetics
Apoptosis Regulatory Proteins metabolism
Baculoviral IAP Repeat-Containing 3 Protein
Cells, Cultured
Fructose-Bisphosphate Aldolase genetics
Fructose-Bisphosphate Aldolase metabolism
Glucose metabolism
Glucose Transporter Type 1 metabolism
Humans
Hypoxia metabolism
Hypoxia-Inducible Factor 1 antagonists & inhibitors
Hypoxia-Inducible Factor 1 genetics
Inhibitor of Apoptosis Proteins genetics
Inhibitor of Apoptosis Proteins metabolism
Proto-Oncogene Proteins c-bcl-2 genetics
Proto-Oncogene Proteins c-bcl-2 metabolism
RNA, Small Interfering pharmacology
Ubiquitin-Protein Ligases
Apoptosis genetics
Glucose Transporter Type 1 genetics
Hypoxia genetics
Hypoxia-Inducible Factor 1 physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0950-9232
- Volume :
- 26
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 17043658
- Full Text :
- https://doi.org/10.1038/sj.onc.1210008