Rapid inhibition of MAPK signaling and anti-proliferation effect via JAK/STAT signaling by interferon-α in hepatocellular carcinoma cell lines

Inamura, Kentaro; Matsuzaki, Yasushi; Uematsu, Naoya; Honda, Akira; Tanaka, Naomi; Uchida, Keiji

doi:10.1016/j.bbamcr.2005.06.003

Cited by 39 publications

(29 citation statements)

References 31 publications

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“…In a hepatocellular carcinoma cell (HCC) study, JAK/STAT activated by interferon-α inhibited MAPK signalling by cross-talking with MEK/ERK pathway (36). Our results in sarcoma suggest this may be due to IFNα induced alteration of the balance between STAT1 and STAT3/ STAT5 favouring inhibition of proliferation and subsequent apoptosis (37).…”

Section: Biology Of Stat3mentioning

confidence: 56%

STAT3 inhibition, a novel approach to enhancing targeted therapy in human cancers

Wang

Crowe

Goldstein

et al. 2012

International Journal of Oncology

179

140

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Section: Biology Of Stat3mentioning

confidence: 56%

STAT3 inhibition, a novel approach to enhancing targeted therapy in human cancers

Wang

Crowe

Goldstein

et al. 2012

International Journal of Oncology

179

140

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“…Cells (7x10 5 ) were harvested at indicated times and lysed with lysis buffer containing 1% Triton X-100, 50 mM Tris (pH 7.5), 10 mM EDTA, 0.02% NaN 3 , and protease inhibitor cocktail (Sigma-Aldrich). The membrane (Millipore, Billerica, MA, USA) was blocked with 5% skim milk in TBS-T [50 mM Tris, 150 mM NaCl and 0.05% Tween-20, (pH 7.6)] at room temperature for 1 h and probed with primary antibodies at 4˚C overnight.…”

Section: Methodsmentioning

confidence: 99%

“…Cells (7x10 5 ) were treated with GW6471 or fludarabine for 1 h before IFN-α and fluoxetine, and then harvested at day 1 for performing ICE-family proteases/ caspases activation to initiate apoptosis. The caspase-3/CPP32 colorimetric assay kit (BioVision, Inc., Milpitas, CA, USA) was used according to the manufacturer's protocols and measured with a spectrophotometer at 405 nm.…”

Section: Methodsmentioning

confidence: 99%

“…IFN-α-induced apoptosis possibly activates the caspase cascade mediated by mitogen-activated protein kinases (1,3,4). Alternatively, IFN-α activates its receptors and induces antiproliferative signaling via the STAT by cross-talking with the extracellular signal-regulated kinase (ERK) pathway; it further leads to the slowing down of G1/S transition without apoptosis in human hepatocellular carcinoma cells (HCC) (5). Conversely, IFN-α reduces activation of ERK in haematological malignancies (6).…”

Section: Introductionmentioning

confidence: 99%

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Fluoxetine regulates cell growth inhibition of interferon-α

Lin¹,

Chiu

et al. 2016

International Journal of Oncology

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Abstract. Fluoxetine, a well-known anti-depression agent, may act as a chemosensitizer to assist and promote cancer therapy. However, how fluoxetine regulates cellular signaling to enhance cellular responses against tumor cell growth remains unclear. In the present study, addition of fluoxetine promoted growth inhibition of interferon-alpha (IFN-α) in human bladder carcinoma cells but not in normal uroepithelial cells through lessening the IFN-α-induced apoptosis but switching to cause G1 arrest, and maintaining the IFN-α-mediated reduction in G2/M phase. Activations and signal transducer and transactivator (STAT)-1 and peroxisome proliferator-activated receptor alpha (PPAR-α) were involved in this process. Chemical inhibitions of STAT-1 or PPAR-α partially rescued bladder carcinoma cells from IFN-α-mediated growth inhibition via blockades of G1 arrest, cyclin D1 reduction, p53 downregulation and p27 upregulation in the presence of fluoxetine. However, the functions of both proteins were not involved in the control of fluoxetine over apoptosis and maintained the declined G2/M phase of IFN-α. These results indicated that activation of PPAR-α and STAT-1 participated, at least in part, in growth inhibition of IFN-α in the presence of fluoxetine.

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“…Our data demonstrate that overexpressing the LKB1 gene inhibits the activation of ERK1/2 and STAT3 proteins in the transfected A549 cells. Some studies demonstrated that one of the subtypes of MAPK could phosphorylate STAT3, which suggested cross-talk between MAPK cascades and JAK-STAT pathways (24,30). It is also now clear that the cross-talk of these pathways contributes to the final proliferation effect on target cells by promoting G1-S phase cell cycle progression.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of the LKB1 gene inhibits lung carcinoma cell proliferation partly through degradation of c-myc protein

Liu

Nan²,

Li³

et al. 2009

Oncol Rep

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Abstract. LKB1 encodes a serine/threonine kinase generally inactivated in human lung cancers, which mediates cancer cell proliferation, migration and differentiation, but its biological function has not been completely elucidated. In this study, we demonstrated that LKB1 was associated with a substantial reduction of c-myc expression by using an inducible LKB1 expression system in the LKB1-null lung cell line A549. Nevertheless, the reduction of the c-Myc gene expression was not accompanied by corresponding reduction of mRNAs but protein, which can be abrogated by a proteosome inhibitor (MG132), suggesting that the reduction was associated with their increased degradation rather than transcriptional controls. Our results implied that the expression of c-Myc protein decreased by LKB1 in transfected cells may be a contributory factor in the process of cell proliferation. Overexpression of the LKB1 gene could inhibit the activation of ERK1/2 and STAT3 signaling pathways involved in the cell proliferation. Thus, LKB1-induced functional operation on c-Myc in promoting cell proliferation may occur in a novel mechanism, which may be regulated by ERK1/2 and/or STAT3 signal pathways in human lung carcinoma cells. Furthermore, our results give some insights into the understanding of how LKB1 inactivation contributes to lung carcinogenesis and emphasizes the central role played by LKB1 in lung cancer development. IntroductionLKB1 (also termed as STK11) gene is deleted or mutated in many human cancers. The functional loss of LKB1 or LKB1-inactivating mutations are known to be correlated with more than one-third of sporadic lung adenocarcinomas (1,2), indicating that LKB1 gene inactivation is critical in lung cancer development, but its biological function has not been completely elucidated. The LKB1 protein has been shown to be involved in the inhibition of cell proliferation, which may participate in the regulation of cell growth in tumor cells by delaying the progression from G0-G1 to S phase of the cell cycle (3-6). The growth inhibitory effect in tumor cells is also mediated through the signaling of cytoplasmic LKB1 and/or the expression reduction of related proteins, such as p27, cyclin D and some transcription factors (7-9). The cellular Myc gene (c-Myc), which can initiate and maintain the transfected status of cells (10,11), is one of the most frequently implicated target genes in carcinogenesis. Deregulated expression of the structurally unaltered Myc protein is sufficient to drive continuous cell proliferation and apoptosis in response to growth-promoting and growthinhibitory signals, respectively (12). Partanen and co-workers (13) have shown that disruption of epithelial cell organization by the lack of proper microenvironment or silencing of LKB1 could restore the ability of c-Myc to reinitiate the cell cycle and induce apoptosis. LKB1 might facilitate a functional operation on c-Myc that contributes to lung cancer development. However, there have been no published studies examining the direct relationship betwe...

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Rapid inhibition of MAPK signaling and anti-proliferation effect via JAK/STAT signaling by interferon-α in hepatocellular carcinoma cell lines

Cited by 39 publications

References 31 publications

STAT3 inhibition, a novel approach to enhancing targeted therapy in human cancers

STAT3 inhibition, a novel approach to enhancing targeted therapy in human cancers

Fluoxetine regulates cell growth inhibition of interferon-α

Overexpression of the LKB1 gene inhibits lung carcinoma cell proliferation partly through degradation of c-myc protein

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