Interferon&amp;ndash;Alpha Suppresses the Antiapoptotic Effect of NF&amp;ndash;kB and Sensitizes Renal Cell Carcinoma Cells in vitro to Chemotherapeutic Drugs

Steiner, Th.; Junker, U.; Henzgen, B.; Nuske, K.; Durum, Scott K.; Schubert, J.

doi:10.1159/000052489

Cited by 30 publications

(16 citation statements)

References 18 publications

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“…TNF on the p65 subunit of NF-jB might be due to enhanced expression of interferons (IFN-a, IFN-b & IFN-c) in these cells, which act on NF-jB through a negative feedback mechanism by inhibiting IjB kinase activity [24,25]. These results are in agreement with earlier findings demonstrating the ability of interferon to downregulate the constitutively active NF-jB in many cancerous cell lines, thus inhibiting its pro-survival effects [26][27][28]. Previous studies have also demonstrated enhanced antitumor activity of TNF-a when combined with interferons in malignant cell lines [29,30].…”

Section: Discussionsupporting

confidence: 91%

HN protein of Newcastle disease virus sensitizes HeLa cells to TNF-α-induced apoptosis by downregulating NF-κB expression

et al. 2016

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Newcastle disease virus (NDV) is an oncolytic virus which selectively replicates in tumor cells and exerts anti-tumor cytotoxic activity by promoting cell death. In this study, we focus on characterization of the underlying mechanisms of NDV-induced cell death in HeLa cells. We find that NDV Herts/33 strain triggers both extrinsic and intrinsic apoptosis at late infection times. The activation of NF-кB pathway and subsequent up-regulation of TNF-α/TRAIL initiates extrinsic apoptosis, leading to activation of caspase 8 and cleavage of Bid into tBid. tBid transmits the extrinsic apoptotic signals to mitochondria and mediates intrinsic apoptosis, which is hallmarked by cleavage of caspase 9. Moreover, RIP1 is cleaved into RIP1-N and RIP1-C at D324 by caspase 8, and this cleavage promotes apoptosis. Surprisingly, over expression of RIP1 reduces apoptosis and depletion of RIP1 promotes apoptosis, suggesting full length RIP1 is anti-apoptotic. Moreover, necroptosis hallmark protein MLKL is activated by phosphorylation at 12-24 h.p.i., and RIP1 regulates the level of phosphor-MLKL. Immunostaining shows that RIP1 aggregates to stress granules (SGs) at 8-24 h.p.i., and phosphor-MLKL is also recruited to SGs, instead of migrating to plasma membrane to exert its necrotic function. Immunoprecipitation study demonstrates that RIP1 bind to phosphor-MLKL, and depletion of RIP1 reduces the aggregation of MLKL to SGs, suggesting that RIP1 recruits MLKL to SGs. Altogether, NDV infection initiates extrinsic apoptosis via activation of NF-кB and secretion of TNF-α/TRAIL. Activation of caspase 8 by TNF-α/TRAIL and subsequent cleavage of Bid and RIP1 transmit the death signals to mitochondria. Meanwhile, virus subverts the host defensive necroptosis via recruiting phosphor-MLKL by RIP1 to SGs. Thus, RIP1 is a central signaling protein in regulation of apoptosis and necroptosis during NDV infection. www.impactjournals.com/oncotarget/

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Section: Discussionsupporting

confidence: 91%

HN protein of Newcastle disease virus sensitizes HeLa cells to TNF-α-induced apoptosis by downregulating NF-κB expression

et al. 2016

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“…The limited efficacy of IFN in the treatment of cancers may result from its induction of cell survival signals through an NF-κB-dependent pathway (21). Other investigators demonstrated a reduction in the TNF-·-mediated NF-κB activation by IFN-Á (22). Our results may be explained in part by the further suppression of NF-κB by the synergistic effects of the combined IFN-Á and DHMEQ treatment.…”

Section: Discussionmentioning

confidence: 53%

Survivin associates with cell proliferation in renal cancer cells: Regulation of survivin expression by insulin-like growth factor-1, interferon-γ and a novel NF-κB inhibitor

Sato

Oya²,

Ito

et al. 2006

Int J Oncol

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Abstract. Although survivin has been widely recognized as an attractive target for cancer therapy, the exact mechanism regarding the regulation of survivin and its effect on cell proliferation have yet to be clearly defined in renal cell carcinoma (RCC). We investigated herein the association between survivin expression and cell proliferation in a RCC cell line, KU19-20. In KU19-20 cells, cell proliferation and survivin expression were significantly induced by IGF-1, whereas they were inhibited by a novel NF-κB inhibitor dehydroxymethyl-epoxyquinomicin (DHMEQ) and IFN-Á. The combination of DHMEQ and IFN-Á inhibited cell proliferation synergistically with a pronounced attenuation of survivin expression. Furthermore, treatment with survivinspecific siRNA reduced expression of survivin and significantly inhibited cell proliferation. Survivin expression was thus associated with cell proliferation in KU19-20 cells. The regulation of survivin by IFN-Á and/or an NF-κB inhibitor may therefore be a potential treatment modality for RCC.

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“…Specifically, NF-jB activation in response to gemcitabine has already been described in cancer cell lines [26][27][28], and it has been shown to be a potential mechanism of cell survival after treatment [13,25]. Moreover, high basal levels of NF-jB have been related with resistance to this agent in pancreatic carcinoma cell lines [13,29,30].…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiling of breast cancer cells in response to gemcitabine: NF-κB pathway activation as a potential mechanism of resistance

Hernández-Vargas

Rodríguez‐Pinilla

Julián-Tendero

et al. 2006

Breast Cancer Res Treat

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Gemcitabine is a nucleoside analog with clinical relevance in the treatment of several solid tumors, including breast carcinoma. In spite of its cytotoxic effect, clinical efficacy is impaired by the development of resistance. We performed gene expression analysis to shed light into the molecular mechanism of action of this drug in two breast cancer cell lines. Activation of genes related with cell cycle, cell growth and apoptosis (BNIP3L, CCNG2, DDIT4, TGFB2, TP53BP1, TP53INP1, and VEGF) was the main finding in the p53-wild type cell line MCF7, while the p53-non-functional cell line MDA-MB-231 was characterized by the regulation of NF-kappaB target genes (BIRC3, CXCL1/GRO1, IRAK2, TNF, TNFAIP and TRAF1). Genes consistently induced (ATF3, CCNG2, CDKN1A, EGR1, INSIG1, and MAF) or repressed (CCND1 and VGF) in both cell lines, were also found after gemcitabine treatment. In addition, MDA-MB-231 cells showed a higher basal and induced NF-kappaB transcriptional activity after treatment with gemcitabine. In comparison with gemcitabine, gene expression after 5-fluorouracil treatment showed essentially different profiles in both cell lines. This, in spite of using equitoxic concentrations producing similar effects on cell cycle. NF-kappaB transcriptional activity in MDA-MB-231 cells was dependent on IkappaB-alpha phosphorylation, as shown by functional experiments using the specific inhibitor BAY11-7082. Moreover, immunohistochemical analysis of clinical samples of breast carcinoma further validated the induction of NF-kappaB expression and IkappaB down-regulation upon neoadjuvant gemcitabine treatment. Thus, gene expression patterns, in vitro functional studies and analysis of tissue samples are in agreement with a role for NF-kappaB pathway in gemcitabine response. Together with the reported role for NF-kappaB in the induction of resistance to chemotherapy, our data gives support to clinical strategies combining gemcitabine with NF-kappaB inhibitors in breast cancer.

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Interferon–Alpha Suppresses the Antiapoptotic Effect of NF–kB and Sensitizes Renal Cell Carcinoma Cells in vitro to Chemotherapeutic Drugs

Cited by 30 publications

References 18 publications

HN protein of Newcastle disease virus sensitizes HeLa cells to TNF-α-induced apoptosis by downregulating NF-κB expression

HN protein of Newcastle disease virus sensitizes HeLa cells to TNF-α-induced apoptosis by downregulating NF-κB expression

Survivin associates with cell proliferation in renal cancer cells: Regulation of survivin expression by insulin-like growth factor-1, interferon-γ and a novel NF-κB inhibitor

Gene expression profiling of breast cancer cells in response to gemcitabine: NF-κB pathway activation as a potential mechanism of resistance

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