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Effects of stem cell factor on hypoxia-inducible factor 1 alpha accumulation in human acute myeloid leukaemia and LAD2 mast cells.

Gibbs BF, Yasinska IM, Oniku AE, Sumbayev VV - PLoS ONE (2011)

Bottom Line: However, the mechanisms of this pathophysiological effect remain unclear.We demonstrated that LAD2 cells have a more robust glutathione (GSH)-dependent antioxidative system compared to THP-1 cells and are therefore protected against the actions of ROS generated in an SCF-dependent manner.BSO-induced GSH depletion led to a significant decrease in HIF-1α prolyl hydroxylase (PHD) activity in THP-1 cells and to near attenuation of it in LAD2 cells.

View Article: PubMed Central - PubMed

Affiliation: Medway School of Pharmacy, University of Kent, Kent, United Kingdom. B.F.Gibbs@kent.ac.uk

ABSTRACT
Stem cell factor (SCF) is a hematopoietic growth factor that exerts its activity by signalling through the tyrosine kinase receptor known as Kit or CD117. SCF-Kit signalling is crucial for the survival, proliferation and differentiation of hematopoietic cells of myeloid lineage. Furthermore, since myeloid leukaemia cells express the Kit receptor, SCF may play an important role in myeloid leukaemia progression too. However, the mechanisms of this pathophysiological effect remain unclear. Recent evidence shows that SCF triggers accumulation of the inducible alpha subunit of hypoxia-inducible factor 1 (HIF-1) in hematopoietic cells--a transcription complex that plays a pivotal role in cellular adaptation to low oxygen availability. However, it is unknown how SCF impacts on HIF-1α accumulation in human myeloid leukaemia and mast cells. Here we show that SCF induces HIF-1α accumulation in THP-1 human myeloid leukaemia cells but not in LAD2 mast cells. We demonstrated that LAD2 cells have a more robust glutathione (GSH)-dependent antioxidative system compared to THP-1 cells and are therefore protected against the actions of ROS generated in an SCF-dependent manner. BSO-induced GSH depletion led to a significant decrease in HIF-1α prolyl hydroxylase (PHD) activity in THP-1 cells and to near attenuation of it in LAD2 cells. In THP-1 cells, SCF-induced HIF-1α accumulation is controlled via ERK, PI3 kinase/PKC-δ/mTOR-dependent and to a certain extent by redox-dependent mechanisms. These results demonstrate for the first time an important cross-talk of signalling pathways associated with HIF-1 activation--an important stage of the myeloid leukaemia cell life cycle.

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Possible mechanisms of SCF-dependent HIF-1α accumulation in human myeloid leukaemia cells. Implication of a GSH-dependent antioxidative system.The scheme demonstrates the involvement of ERK, PI3 kinase/PKC-δ-mTOR, PKC α/β-NADPH oxidase-ROS and XOD pathways in SCF-induced Kit receptor-dependent HIF-1α accumulation in THP-1 human myeloid leukaemia cells. The implication of GSH-dependent antioxidative system and ASK1 in the process is outlined.
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pone-0022502-g007: Possible mechanisms of SCF-dependent HIF-1α accumulation in human myeloid leukaemia cells. Implication of a GSH-dependent antioxidative system.The scheme demonstrates the involvement of ERK, PI3 kinase/PKC-δ-mTOR, PKC α/β-NADPH oxidase-ROS and XOD pathways in SCF-induced Kit receptor-dependent HIF-1α accumulation in THP-1 human myeloid leukaemia cells. The implication of GSH-dependent antioxidative system and ASK1 in the process is outlined.

Mentions: We conclude that SCF leads to a significant accumulation/activation of HIF-1α in human myeloid leukaemia THP-1 cells but not in LAD2 human mast cells. LAD2 cells employ a more powerful GSH-dependent antioxidative system compared to THP-1 myeloid leukaemia cells. LAD2 mast cells are therefore completely protected against action of ROS generated in SCF-mediated manner. In both cases GSH plays an ROS scavenging role. BSO-induced GSH depletion leads to a significant decrease in PHD activity in THP-1 cells and to near attenuation of it in LAD2 cells. In THP-1 cells SCF-induced HIF-1α accumulation is controlled via ERK, PI3 kinase/PKC-δ/mTOR-dependent and to certain extent by a redox-dependent mechanisms. Additionally, XOD contributes to SCF-induced mTOR accumulation, while it is also known to produce superoxide anion-radicals. These mechanisms are summarised in the scheme presented in the Figure 7.


Effects of stem cell factor on hypoxia-inducible factor 1 alpha accumulation in human acute myeloid leukaemia and LAD2 mast cells.

Gibbs BF, Yasinska IM, Oniku AE, Sumbayev VV - PLoS ONE (2011)

Possible mechanisms of SCF-dependent HIF-1α accumulation in human myeloid leukaemia cells. Implication of a GSH-dependent antioxidative system.The scheme demonstrates the involvement of ERK, PI3 kinase/PKC-δ-mTOR, PKC α/β-NADPH oxidase-ROS and XOD pathways in SCF-induced Kit receptor-dependent HIF-1α accumulation in THP-1 human myeloid leukaemia cells. The implication of GSH-dependent antioxidative system and ASK1 in the process is outlined.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3140519&req=5

pone-0022502-g007: Possible mechanisms of SCF-dependent HIF-1α accumulation in human myeloid leukaemia cells. Implication of a GSH-dependent antioxidative system.The scheme demonstrates the involvement of ERK, PI3 kinase/PKC-δ-mTOR, PKC α/β-NADPH oxidase-ROS and XOD pathways in SCF-induced Kit receptor-dependent HIF-1α accumulation in THP-1 human myeloid leukaemia cells. The implication of GSH-dependent antioxidative system and ASK1 in the process is outlined.
Mentions: We conclude that SCF leads to a significant accumulation/activation of HIF-1α in human myeloid leukaemia THP-1 cells but not in LAD2 human mast cells. LAD2 cells employ a more powerful GSH-dependent antioxidative system compared to THP-1 myeloid leukaemia cells. LAD2 mast cells are therefore completely protected against action of ROS generated in SCF-mediated manner. In both cases GSH plays an ROS scavenging role. BSO-induced GSH depletion leads to a significant decrease in PHD activity in THP-1 cells and to near attenuation of it in LAD2 cells. In THP-1 cells SCF-induced HIF-1α accumulation is controlled via ERK, PI3 kinase/PKC-δ/mTOR-dependent and to certain extent by a redox-dependent mechanisms. Additionally, XOD contributes to SCF-induced mTOR accumulation, while it is also known to produce superoxide anion-radicals. These mechanisms are summarised in the scheme presented in the Figure 7.

Bottom Line: However, the mechanisms of this pathophysiological effect remain unclear.We demonstrated that LAD2 cells have a more robust glutathione (GSH)-dependent antioxidative system compared to THP-1 cells and are therefore protected against the actions of ROS generated in an SCF-dependent manner.BSO-induced GSH depletion led to a significant decrease in HIF-1α prolyl hydroxylase (PHD) activity in THP-1 cells and to near attenuation of it in LAD2 cells.

View Article: PubMed Central - PubMed

Affiliation: Medway School of Pharmacy, University of Kent, Kent, United Kingdom. B.F.Gibbs@kent.ac.uk

ABSTRACT
Stem cell factor (SCF) is a hematopoietic growth factor that exerts its activity by signalling through the tyrosine kinase receptor known as Kit or CD117. SCF-Kit signalling is crucial for the survival, proliferation and differentiation of hematopoietic cells of myeloid lineage. Furthermore, since myeloid leukaemia cells express the Kit receptor, SCF may play an important role in myeloid leukaemia progression too. However, the mechanisms of this pathophysiological effect remain unclear. Recent evidence shows that SCF triggers accumulation of the inducible alpha subunit of hypoxia-inducible factor 1 (HIF-1) in hematopoietic cells--a transcription complex that plays a pivotal role in cellular adaptation to low oxygen availability. However, it is unknown how SCF impacts on HIF-1α accumulation in human myeloid leukaemia and mast cells. Here we show that SCF induces HIF-1α accumulation in THP-1 human myeloid leukaemia cells but not in LAD2 mast cells. We demonstrated that LAD2 cells have a more robust glutathione (GSH)-dependent antioxidative system compared to THP-1 cells and are therefore protected against the actions of ROS generated in an SCF-dependent manner. BSO-induced GSH depletion led to a significant decrease in HIF-1α prolyl hydroxylase (PHD) activity in THP-1 cells and to near attenuation of it in LAD2 cells. In THP-1 cells, SCF-induced HIF-1α accumulation is controlled via ERK, PI3 kinase/PKC-δ/mTOR-dependent and to a certain extent by redox-dependent mechanisms. These results demonstrate for the first time an important cross-talk of signalling pathways associated with HIF-1 activation--an important stage of the myeloid leukaemia cell life cycle.

Show MeSH
Related in: MedlinePlus