1. Activation of hypoxia-inducible factor 1 in human T-cell leukaemia virus type 1-infected cell lines and primary adult T-cell leukaemia cells
- Author
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Takehiro Matsuda, Gregg L. Semenza, Mariko Tomita, Jun Nosuke Uchihara, Yuetsu Tanaka, Naoki Mori, C. Michiels, Kazuiku Ohshiro, Taeko Okudaira, and Naoya Taira
- Subjects
Adult ,Hypoxia-Inducible Factor 1 ,Small interfering RNA ,Leukemia, T-Cell ,Mutant ,Biology ,Biochemistry ,Virus ,Phosphatidylinositol 3-Kinases ,chemistry.chemical_compound ,Infected cell ,Tumor Cells, Cultured ,Humans ,Retraction Articles ,LY294002 ,Adult T-cell leukaemia ,Phosphorylation ,RNA, Small Interfering ,Protein Kinase Inhibitors ,Molecular Biology ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Phosphoinositide-3 Kinase Inhibitors ,Human T-lymphotropic virus 1 ,Gene knockdown ,DNA ,Gene Products, tax ,Cell Biology ,Hypoxia-Inducible Factor 1, alpha Subunit ,Virology ,Cell biology ,Enzyme Activation ,Gene Expression Regulation, Neoplastic ,Vascular endothelial growth factor ,chemistry ,Virus type ,Retraction Article ,Proto-Oncogene Proteins c-akt ,T cell leukaemia ,Protein Binding ,Signal Transduction ,Research Article - Abstract
HTLV-1 (human T-cell leukaemia virus type 1) is the causative agent for ATL (adult T-cell leukaemia). HTLV-1 Tax can activate the PI3K (phosphoinositide 3-kinase)/Akt signalling pathway, which is responsible for survival of HTLV-1-infected T-cells. HIFs (hypoxia-inducible factors) are transcriptional regulators that play a central role in the response to hypoxia. Overexpression of HIF-1alpha in many cancers is associated with a poor response to treatment and increased patient mortality. Our objectives in the present study were to investigate whether HIF-1 was activated in HTLV-1-infected T-cells and to elucidate the molecular mechanisms of HIF-1 activation by focusing on the PI3K/Akt signalling pathway. We detected a potent pathway that activated HIF-1 in the HTLV-1-infected T-cells under a normal oxygen concentration. Enhanced HIF-1alpha protein expression and HIF-1 DNA-binding activity were exhibited in HTLV-1-infected T-cell lines. Knockdown of HIF-1alpha by siRNA (small interfering RNA) suppressed the growth and VEGF (vascular endothelial growth factor) expression of the HTLV-1-infected T-cell line. HIF-1 protein accumulation and transcriptional activity were enhanced by Tax, which was inhibited by dominant-negative Akt. Importantly, mutant forms of Tax that are defective in activation of the PI3K/Akt pathway failed to induce HIF-1 transcriptional activity. The PI3K inhibitor LY294002 suppressed HIF-1alpha protein expression, HIF-1 DNA-binding and HIF-1 transcriptional activity in HTLV-1-infected T-cell lines. In primary ATL cells, HIF-1alpha protein levels were strongly correlated with levels of phosphorylated Akt. The results of the present study suggest that PI3K/Akt activation induced by Tax leads to activation of HIF-1. As HIF-1 plays a major role in tumour progression, it may represent a molecular target for the development of novel ATL therapeutics.
- Published
- 2007