FoxO3a mediates transforming growth factor-β1-induced apoptosis in FaO rat hepatoma cells

Kim, Byung-Chul

doi:10.5483/bmbrep.2008.41.10.728

Cited by 10 publications

(9 citation statements)

References 25 publications

(23 reference statements)

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“…[21] suggest that, in mesangial cells, decreased FoxO3a transcriptional activity as a result of TGF‐β1 may lead to the progression of diabetic nephropathy. However, TGF‐β1/FoxO3a signalling appears to be cell‐type specific and possibly disease state‐specific [37]. The data of the present study demonstrate that TGF‐β1 decreases FoxO3a‐regulated gene expression in HK‐2 cells, as previously shown in mesangial cells [21].…”

Section: Discussionsupporting

confidence: 83%

Insulin receptor substrate 2 and FoxO3a signalling are involved in E‐cadherin expression and transforming growth factor‐β1‐induced repression in kidney epithelial cells

et al. 2011

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Insulin receptor substrate (IRS) proteins comprise a family of adaptor molecules that integrate extracellular signals from insulin and other ligands to intracellular effectors such as phosphoinositide 3-kinase and mitogenactivated protein kinase. The predominant forms of IRS protein in humans, IRS1 and IRS2, are widely expressed. Despite structural similarities, IRS1 and IRS2 display distinct signalling modalities, and mice lacking these proteins present with distinct phenotypes. Transforming growth factor (TGF)-b1 is the primary cytokine shown to induce epithelial-mesenchymal transition. Recent data have demonstrated a role for IRS1 in TGFb1-induced epithelial-mesenchymal transition in lung epithelial cells. In the present study, we report data showing that TGF-b1 signals via IRS2 in kidney epithelial cells. Small interfering RNA (siRNA)-mediated targeting of IRS2 increased E-cadherin expression, although it did not alter TGF-b1-mediated E-cadherin repression. Phosphorylation of the downstream target of IRS2 ⁄ Akt signalling, FoxO3a, was induced on Ser253 and, to a lesser extent, on Thr32. Transfection of FoxO3aThr32Ala mutant for 24 h greatly reduced FoxO3a phosphorylation on Ser253 but over-expression of FoxO3a Ser253Ala did not effect Thr32 phosphorylation, suggesting that a distinct order of phosphorylation of FoxO3a is required for physiological function in cells. Transfection of FoxO3a Ser253Ala mutant partially inhibited TGF-b1-mediated E-cadherin repression at 24 h. Taken together, these data highlight novel roles for IRS2 and FoxO3a in the regulation of kidney epithelial cells by E-cadherin.

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Section: Discussionsupporting

confidence: 83%

Insulin receptor substrate 2 and FoxO3a signalling are involved in E‐cadherin expression and transforming growth factor‐β1‐induced repression in kidney epithelial cells

et al. 2011

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“…Human hepatoma cells have been shown to exhibit high expression and enhanced activity of Akt [17]. It is noteworthy that FOXO3a and Akt-regulated transcription factor have been found to be functionally important in the development of human HCC [20][21][22]. To our knowledge, we are the first to report the downregulated expression of p-Akt of HepG2 cells treated with higher concentrations of [19] stated similar results on neuroblastoma cells that IFN-b downregulates PI3K/Akt pathway.…”

Section: Discussionsupporting

confidence: 68%

“…In consistence with previously identified significance of the Akt oncogenic kinase in HCC, our data indicate that Akt phosphorylation inhibited by IFNb is associated with reducing Akt activation. It is noteworthy that FOXO3a and Akt-regulated transcription factor have been found to be functionally important in the development of human HCC [20][21][22]. Xie et al [23] reported the association of suppression of Akt activity and enhanced transcriptional activity of FOXO3a in the cells treated with IFN-b.…”

Section: Dose-dependent Activation Of Caspases 3 and 9 In Cells Treatmentioning

confidence: 99%

Inhibitory effects of interferon‐β on hepatocellular carcinoma HepG2 via Akt/STAT phosphorylation

Ethiraj

Veerappan²,

Samuel³

et al. 2015

Fundamemntal Clinical Pharma

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Conventional chemotherapy fails to cure metastatic hepatoma mainly due to its high hepatotoxicity. Currently, doxorubicin is the most widely used drug against liver cancer either as single agent or in combination with other chemotherapeutics such as cisplatin. It is limited due to their severe toxicity on normal hepatocytes. Therefore, alternative therapeutic agents without or with low hepatotoxicity are highly desirable. Interferons are a family of cytokines that potently demonstrate antiviral, immunomodulatory, and antiproliferative activities. It also exerts direct cytotoxic effects on tumor cells. The purpose of this study was to examine the in vitro cytotoxicity of interferon-β on HepG2 cells. We revealed the presence of binding receptor of interferon-β in HepG2 cells. The dose-dependent inhibition on cell proliferation was observed. We demonstrated that IFN-β exhibited significant cytotoxicity in HepG2 cells mainly through phosphorylation of signal transducers and activators of transcription 2. The activation of Akt was suppressed. The stimulation of pro-apoptotic protein expression of Bax, inhibition of anti-apoptotic protein expression of Bcl-2, activation of cleaved caspases 9 and 3 was found at increasing concentrations. In conclusion, our results suggest that interferon-β has potential to inhibit cell proliferation dose dependently. Increased concentrations of interferon-β influenced apoptosis via mitochondrial pathway through inhibition of p-Akt.

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“…In consistence with previously identified significance of the Akt oncogenic kinase in HCC, our data indicate that FOXO3a phosphorylation inhibited by BMSC/IFN- β is associated with reducing Akt activation. It is noteworthy that FOXO3a and Akt-regulated transcription factor have been found to be functionally important in the development of human HCC (Saxena et al , 2007; Kim, 2008; Lu et al , 2009). These new data not only provide a line of evidence for the regulatory effect of BMSC/IFN- β on Akt phosphorylation, but also link the BMSC/IFN- β -triggered Akt signalling cascade inhibition with the lowly proliferative phenotype of HCC cells.…”

Section: Discussionmentioning

confidence: 99%

Interferon-β gene-modified human bone marrow mesenchymal stem cells attenuate hepatocellular carcinoma through inhibiting AKT/FOXO3a pathway

Xie

Lin

et al. 2013

Br J Cancer

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Objective:This study aims to investigate the using of bone marrow mesenchymal stem cells (BMSCs) genetically engineered to produce interferon-β (IFN-β) as a gene delivery system to treat hepatocellular carcinoma (HCC) in vitro and in vivo.Methods:To measure the effects on tumour cell growth in vitro, IFN-β-producing BMSCs (BMSC/IFN-β) were co-cultured with the HCC cell line HepG2 and Huh7. Enzyme-linked immunosorbent assay (ELISA) was used to detect the IFN-β secretion in the BMSC culture condition medium (CM). The effect of BMSC/IFN-β on HCC cells proliferation was examined both in vitro and in vivo by using MTT, colony formation assay, BrdU staining, cell cycle analysis, and xenografted NOD/SCID mouse tumour model. To examine the impact of BMSC/IFN-β on the AKT/FOXO3a signalling, RT–PCR and western blotting were performed.Results:The BMSC/IFN-β cells can stably secrete high levels of IFN-β. Both MTT and colony forming assay showed that HCC cells had a lower growth rate when cultured in BMSC/IFN-β-CM as compared with that in BMSC/vector-CM or DMEM culture group. Co-culture with BMSC/IFN-β-CM dramatically decreased the percentages of cells with incorporated BrdUrd. In BMSC/IFN-β-CM-treated HCC cells, the proportion of G1-phase cells increased but it decreased in the S phase of the cell. The BMSC/IFN-β inhibited HCC growth in NOD/SCID mice and proved the survival period of these mice. Compared with the control group, p21 and p27 expression of hepatoma cells increased, whereas cyclin D1 and phosphorylation of Rb expression decreased when co-cultured with BMSC/IFN-β-CM. It was associated with suppression of Akt activity and enhanced transcriptional activity of FOXO3a.Conclusion:The IFN-β gene-modified BMSCs can effectively inhibit the proliferation of HCC cells in vitro and in vivo through inhibiting AKT/FOXO3a pathway. These results indicate that BMSC/IFN-β are a powerful anticancer cytotherapeutic tool for HCC.

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FoxO3a mediates transforming growth factor-β1-induced apoptosis in FaO rat hepatoma cells

Cited by 10 publications

References 25 publications

Insulin receptor substrate 2 and FoxO3a signalling are involved in E‐cadherin expression and transforming growth factor‐β1‐induced repression in kidney epithelial cells

Insulin receptor substrate 2 and FoxO3a signalling are involved in E‐cadherin expression and transforming growth factor‐β1‐induced repression in kidney epithelial cells

Inhibitory effects of interferon‐β on hepatocellular carcinoma HepG2 via Akt/STAT phosphorylation

Interferon-β gene-modified human bone marrow mesenchymal stem cells attenuate hepatocellular carcinoma through inhibiting AKT/FOXO3a pathway

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