Activation of hypoxia-inducible factor 1 in human T-cell leukaemia virus type 1-infected cell lines and primary adult T-cell leukaemia cells

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.

Activation of the Oxidative Stress Pathway by HIV-1 Vpr Leads to Induction of Hypoxia-inducible Factor 1α Expression

“…In this regard, it has been shown that HIF-1␣ can be induced and accumulated in cells infected with HTLV-1 and HHV8 (46,47). Furthermore, HIF-1␣ was also shown to be suppressed in cells infected with a temperaturesensitive Moloney murine leukemia virus mutant (48).…”

Non-Cancer Uses of Histone Deacetylase Inhibitors: Effects on Infectious Diseases and β-Hemoglobinopathies+

“…This apoptosis is related to a reduction of the DNA binding of NF-B and AP-1 and to a down-regulation of Bcl-x L and cyclin D2 expression in HTLV-1-infected T-cells [55]. The same apoptosis effect could be related to inhibition of HIF-1 by HDACi able to inhibit the class II HDACs [56], because HIF-1 has been shown to be highly activated in HTLV-1-infected T-cells [57].…”

Targeting Hypoxia-Inducible Factor-1 (HIF-1) Signaling in Therapeutics: Implications for the Treatment of Inflammatory Bowel Disease

“…bacterial interactions can induce HIF-1 signaling in some cells. For example, human T-cell leukaemia virus (HTLV)-1 [19], Epstein-Barr virus [20,21], Hepatitis B virus [22][23][24][25][26] and Kaposi's sarcoma-associated herpes virus [27][28][29] use a variety of molecular strategies to increase HIF-1 expression and/or transcriptional activity. In addition to viruses, a variety of bacteria and their products, especially lipopolysaccharide (LPS), up-regulate HIF-1 expression in a number of cell types [30][31][32][33][34] Fig.…”