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PPAR γ regulated CIDEA affects pro-apoptotic responses in glioblastoma

View Article: PubMed Central - PubMed

ABSTRACT

Refractoriness of glioblastoma multiforme (GBM) to current treatment paradigms has necessitated identification of new targets to better the existing therapeutic strategies. One such target is peroxisome proliferator-activated receptor gamma (PPARγ) – a transcription factor involved in regulation of lipid metabolism and inflammation. Expression of PPARγ, a known regulator of cell death-inducing DFFA-like effector (CIDEA), is modulated by hypoxia inducible factor (HIF-1α). While the involvement of CIDEA in lipid metabolism is known, its role in malignancies remains largely unknown. An elevated PPARγ and low CIDEA level was observed in GBM tumors as compared with surrounding non-neoplastic tissue. As reciprocal relation exists between PPAR and HIF-1α: and as HIF-1α is a key component in glioma progression, their role in regulating CIDEA expression in glioblastoma was investigated. Although HIF-1α inhibition had no effect on CIDEA expression, pharmacological inhibition of PPARγ elevated CIDEA levels. PPARγ mediated upregulation of CIDEA was accompanied by decreased recruitment of NFκB and SP1 to their predicted binding sites on CIDEA promoter. Ectopic expression of CIDEA triggered apoptosis, activated JNK, decreased HIF-1α activation and increased PPARγ levels in glioma cells. While CIDEA overexpression induced actin cytoskeletal disruption, cell cycle arrest, release of pro-inflammatory cytokine IL-6 in a JNK-dependent manner; CIDEA mediated apoptotic cell death, decreased STAT3 phosphorylation and increased p53 acetylation was JNK independent. This study highlights for the first time the existence of (i) PPARγ-CIDEA regulatory loop in glioma and (ii) novel function of CIDEA as regulator of glioma cell survival.

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Overexpression of CIDEA increases p53 acetylation in a JNK-independent manner. CIDEA overexpression affects acetylated p53 and total p53 levels in the nucleus (a) and the cytosol (b) of glioma cells in a JNK-independent manner. A representative blot is shown from three independent experiments with identical results. Blots were re-probed with C23 (for nuclear extract) or GAPDH (for cytosolic extract) as loading control.
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fig5: Overexpression of CIDEA increases p53 acetylation in a JNK-independent manner. CIDEA overexpression affects acetylated p53 and total p53 levels in the nucleus (a) and the cytosol (b) of glioma cells in a JNK-independent manner. A representative blot is shown from three independent experiments with identical results. Blots were re-probed with C23 (for nuclear extract) or GAPDH (for cytosolic extract) as loading control.

Mentions: As ectopic expression of CIDEA induced cell death, we investigated the status of p53 in CIDEA overexpressing cells. CIDEA induced p53 expression in a JNK-independent manner both in wild-type and mutant p53 glioma cells. Interestingly, p53 was localized in the nucleus of p53 wild-type A172 cells (Figure 5a), whereas a cytosolic localization was observed in p53 mutant cells T98G (Figure 5b). As acetylation of p53 increases its transcriptional activity as well as the transcription independent pro-apoptotic function,22 the status of acetylated p53 in CIDEA overexpressing cells was investigated. Increased acetylation of p53 in cell lines containing transcriptionally active or inactive p53 was observed on CIDEA overexpression (Figures 5a and b).


PPAR γ regulated CIDEA affects pro-apoptotic responses in glioblastoma
Overexpression of CIDEA increases p53 acetylation in a JNK-independent manner. CIDEA overexpression affects acetylated p53 and total p53 levels in the nucleus (a) and the cytosol (b) of glioma cells in a JNK-independent manner. A representative blot is shown from three independent experiments with identical results. Blots were re-probed with C23 (for nuclear extract) or GAPDH (for cytosolic extract) as loading control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4979534&req=5

fig5: Overexpression of CIDEA increases p53 acetylation in a JNK-independent manner. CIDEA overexpression affects acetylated p53 and total p53 levels in the nucleus (a) and the cytosol (b) of glioma cells in a JNK-independent manner. A representative blot is shown from three independent experiments with identical results. Blots were re-probed with C23 (for nuclear extract) or GAPDH (for cytosolic extract) as loading control.
Mentions: As ectopic expression of CIDEA induced cell death, we investigated the status of p53 in CIDEA overexpressing cells. CIDEA induced p53 expression in a JNK-independent manner both in wild-type and mutant p53 glioma cells. Interestingly, p53 was localized in the nucleus of p53 wild-type A172 cells (Figure 5a), whereas a cytosolic localization was observed in p53 mutant cells T98G (Figure 5b). As acetylation of p53 increases its transcriptional activity as well as the transcription independent pro-apoptotic function,22 the status of acetylated p53 in CIDEA overexpressing cells was investigated. Increased acetylation of p53 in cell lines containing transcriptionally active or inactive p53 was observed on CIDEA overexpression (Figures 5a and b).

View Article: PubMed Central - PubMed

ABSTRACT

Refractoriness of glioblastoma multiforme (GBM) to current treatment paradigms has necessitated identification of new targets to better the existing therapeutic strategies. One such target is peroxisome proliferator-activated receptor gamma (PPARγ) – a transcription factor involved in regulation of lipid metabolism and inflammation. Expression of PPARγ, a known regulator of cell death-inducing DFFA-like effector (CIDEA), is modulated by hypoxia inducible factor (HIF-1α). While the involvement of CIDEA in lipid metabolism is known, its role in malignancies remains largely unknown. An elevated PPARγ and low CIDEA level was observed in GBM tumors as compared with surrounding non-neoplastic tissue. As reciprocal relation exists between PPAR and HIF-1α: and as HIF-1α is a key component in glioma progression, their role in regulating CIDEA expression in glioblastoma was investigated. Although HIF-1α inhibition had no effect on CIDEA expression, pharmacological inhibition of PPARγ elevated CIDEA levels. PPARγ mediated upregulation of CIDEA was accompanied by decreased recruitment of NFκB and SP1 to their predicted binding sites on CIDEA promoter. Ectopic expression of CIDEA triggered apoptosis, activated JNK, decreased HIF-1α activation and increased PPARγ levels in glioma cells. While CIDEA overexpression induced actin cytoskeletal disruption, cell cycle arrest, release of pro-inflammatory cytokine IL-6 in a JNK-dependent manner; CIDEA mediated apoptotic cell death, decreased STAT3 phosphorylation and increased p53 acetylation was JNK independent. This study highlights for the first time the existence of (i) PPARγ-CIDEA regulatory loop in glioma and (ii) novel function of CIDEA as regulator of glioma cell survival.

No MeSH data available.


Related in: MedlinePlus