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Paradoxical regulation of hypoxia inducible factor-1α (HIF-1α) by histone deacetylase inhibitor in diffuse large B-cell lymphoma.

Bhalla S, Evens AM, Prachand S, Schumacker PT, Gordon LI - PLoS ONE (2013)

Bottom Line: We show here that HIF-1α expression is constitutively active in multiple diffuse large B cell lymphoma (DLBCL) cell lines under normoxia and it is regulated by the PI3K/AKT pathway.We tested the hypothesis that PCI-24781- induced autophagy is mediated by HIF-1α and that inhibition of HIF-1α in these cells results in attenuation of autophagy and decreased survival.We also provide evidence that autophagy serves as a survival pathway in DLBCL cells treated with PCI-24781 which suggests that the use of autophagy inhibitors such as chloroquine or 3-methyl adenine in combination with PCI-24781 may enhance apoptosis in lymphoma cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Division of Hematology/Oncology Northwestern University Feinberg School of Medicine and the Robert H Lurie Comprehensive Cancer Center, Chicago, Illinois, United States of America.

ABSTRACT
Hypoxia inducible factor (HIF) is important in cancer, as it regulates various oncogenic genes as well as genes involved in cell survival, proliferation, and migration. Elevated HIF-1 protein promotes a more aggressive tumor phenotype, and greater HIF-1 expression has been demonstrated to correlate with poorer prognosis, increased risk of metastasis and increased mortality. Recent reports suggest that HIF-1 activates autophagy, a lysosomal degradation pathway which may promote tumor cell survival. We show here that HIF-1α expression is constitutively active in multiple diffuse large B cell lymphoma (DLBCL) cell lines under normoxia and it is regulated by the PI3K/AKT pathway. PCI-24781, a pan histone deacetylase inhibitor (HDACI), enhanced accumulation of HIF-1α and induced autophagy initially, while extended incubation with the drug resulted in inhibition of HIF-1α. We tested the hypothesis that PCI-24781- induced autophagy is mediated by HIF-1α and that inhibition of HIF-1α in these cells results in attenuation of autophagy and decreased survival. We also provide evidence that autophagy serves as a survival pathway in DLBCL cells treated with PCI-24781 which suggests that the use of autophagy inhibitors such as chloroquine or 3-methyl adenine in combination with PCI-24781 may enhance apoptosis in lymphoma cells.

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Related in: MedlinePlus

PCI-24781-induced suppression in HIF-1α protein does not require proteasomal degradation.OCI-LY3 cells were incubated with indicated concentrations of PCI-24781 or MG132 alone or in combination for 24 hr followed by western blotting using specific antibodies to HIF-1α and HIF-1α-OH.
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pone-0081333-g003: PCI-24781-induced suppression in HIF-1α protein does not require proteasomal degradation.OCI-LY3 cells were incubated with indicated concentrations of PCI-24781 or MG132 alone or in combination for 24 hr followed by western blotting using specific antibodies to HIF-1α and HIF-1α-OH.

Mentions: To explore the underlying mechanisms of PCI-24781-induced suppression of HIF-1α protein, we tested whether this effect is due to increased proteasomal degradation. Under normoxic conditions HIF-1α is hydroxylated at conserved proline residues by prolyl hydroxylases allowing their recognition and ubiquitination by the VHL E3 ubiquitin ligase and rapid degradation by the proteasome [37] . To determine how PCI-24781 enhanced HIF-1α degradation, we treated OCI-LY3 cell line with PCI-24781 and a proteasome inhibitor, MG-132 and analyzed the expression of HIF-1α and hydroxylated HIF-1α protein by immunoblotting. As shown in Figure 3, co-treatment of cells with MG-132 did not inhibit the effect of PCI-24781 on HIF-1α protein or its hydroxylation (hydroxy HIF-1α), suggesting that the decrease in HIF-1α after PCI-24781 treatment is not due to increased degradation through proteasomal activity.


Paradoxical regulation of hypoxia inducible factor-1α (HIF-1α) by histone deacetylase inhibitor in diffuse large B-cell lymphoma.

Bhalla S, Evens AM, Prachand S, Schumacker PT, Gordon LI - PLoS ONE (2013)

PCI-24781-induced suppression in HIF-1α protein does not require proteasomal degradation.OCI-LY3 cells were incubated with indicated concentrations of PCI-24781 or MG132 alone or in combination for 24 hr followed by western blotting using specific antibodies to HIF-1α and HIF-1α-OH.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3842257&req=5

pone-0081333-g003: PCI-24781-induced suppression in HIF-1α protein does not require proteasomal degradation.OCI-LY3 cells were incubated with indicated concentrations of PCI-24781 or MG132 alone or in combination for 24 hr followed by western blotting using specific antibodies to HIF-1α and HIF-1α-OH.
Mentions: To explore the underlying mechanisms of PCI-24781-induced suppression of HIF-1α protein, we tested whether this effect is due to increased proteasomal degradation. Under normoxic conditions HIF-1α is hydroxylated at conserved proline residues by prolyl hydroxylases allowing their recognition and ubiquitination by the VHL E3 ubiquitin ligase and rapid degradation by the proteasome [37] . To determine how PCI-24781 enhanced HIF-1α degradation, we treated OCI-LY3 cell line with PCI-24781 and a proteasome inhibitor, MG-132 and analyzed the expression of HIF-1α and hydroxylated HIF-1α protein by immunoblotting. As shown in Figure 3, co-treatment of cells with MG-132 did not inhibit the effect of PCI-24781 on HIF-1α protein or its hydroxylation (hydroxy HIF-1α), suggesting that the decrease in HIF-1α after PCI-24781 treatment is not due to increased degradation through proteasomal activity.

Bottom Line: We show here that HIF-1α expression is constitutively active in multiple diffuse large B cell lymphoma (DLBCL) cell lines under normoxia and it is regulated by the PI3K/AKT pathway.We tested the hypothesis that PCI-24781- induced autophagy is mediated by HIF-1α and that inhibition of HIF-1α in these cells results in attenuation of autophagy and decreased survival.We also provide evidence that autophagy serves as a survival pathway in DLBCL cells treated with PCI-24781 which suggests that the use of autophagy inhibitors such as chloroquine or 3-methyl adenine in combination with PCI-24781 may enhance apoptosis in lymphoma cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Division of Hematology/Oncology Northwestern University Feinberg School of Medicine and the Robert H Lurie Comprehensive Cancer Center, Chicago, Illinois, United States of America.

ABSTRACT
Hypoxia inducible factor (HIF) is important in cancer, as it regulates various oncogenic genes as well as genes involved in cell survival, proliferation, and migration. Elevated HIF-1 protein promotes a more aggressive tumor phenotype, and greater HIF-1 expression has been demonstrated to correlate with poorer prognosis, increased risk of metastasis and increased mortality. Recent reports suggest that HIF-1 activates autophagy, a lysosomal degradation pathway which may promote tumor cell survival. We show here that HIF-1α expression is constitutively active in multiple diffuse large B cell lymphoma (DLBCL) cell lines under normoxia and it is regulated by the PI3K/AKT pathway. PCI-24781, a pan histone deacetylase inhibitor (HDACI), enhanced accumulation of HIF-1α and induced autophagy initially, while extended incubation with the drug resulted in inhibition of HIF-1α. We tested the hypothesis that PCI-24781- induced autophagy is mediated by HIF-1α and that inhibition of HIF-1α in these cells results in attenuation of autophagy and decreased survival. We also provide evidence that autophagy serves as a survival pathway in DLBCL cells treated with PCI-24781 which suggests that the use of autophagy inhibitors such as chloroquine or 3-methyl adenine in combination with PCI-24781 may enhance apoptosis in lymphoma cells.

Show MeSH
Related in: MedlinePlus