IκBα gene therapy in tumor necrosis factor-α- and chemotherapy-mediated apoptosis of hepatocellular carcinomas

Tietze, Maja Katrin; Wüestefeld, Torsten; Paul, Yasmin; Zender, Lars; Manns, Michael P.; Kubicka, Stefan

doi:10.1038/sj.cgt.0241

Cited by 18 publications

(19 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…48 This finding would indicate that NF-κB could be pro-apoptotic rather than anti-apoptotic in HCC cells. In pancreatic islet β-cells, inactivation of NF-κB by IκBα super-repressor similarly prevents apoptosis.…”

Section: Discussionmentioning

confidence: 97%

NF-κB protects rat ARL-6 hepatocellular carcinoma cells against hydrogen peroxide-induced apoptosis

Qiao¹,

Yu²,

Dent³

et al. 2005

Cancer Biology & Therapy

View full text Add to dashboard Cite

Background/Aims: Refractoriness of some tumours to apoptosis has been related to over-expression of NF-κB, while NF-κB inhibition can promote apoptosis in several cell types. We compared NF-κB activation profiles between normal rat hepatocytes and ARL-6 rat hepatocellular carcinoma (HCC) cells exposed to hydrogen peroxide (H 2 O 2 ), and examined whether NF-κB activation could explain the observed resistance to apoptosis of ARL-6 cells. We then infected ARL-6 cells with recombinant adenovirus containing mutant (non-degradable) IkBa (Adv-mIκBα), and examined whether this rendered ARL-6 cells more sensitive to oxidative stress-induced apoptosis.Methods: Cultured primary rat hepatocytes and ARL-6 cells were treated with graded doses of H 2 O 2 . To block NF-κB, ARL-6 cells were incubated with Adv-mIκBα for 24 h. Cytotoxicity, NF-κB activation, cell proliferation, and apoptosis were determined.Results: H 2 O 2 induced more apoptosis in primary hepatocytes than ARL-6 cells, and the relative resistance of ARL-6 cells to H 2 O 2 -induced apoptosis was associated with more pronounced NF-κB activity. In ARL-6 cells, nuclear translocation of NF-κB took place within 2 h of administering H 2 O 2 and remained prominent at 36 h. Adv-mIκBα sensitized ARL-6 cells to H 2 O 2 -induced apoptosis, but cell proliferation was minimally suppressed.Conclusions: Compared with normal hepatocytes, ARL-6 cells are refractory to apoptosis after exposure to H 2 O 2 , and this is associated with NF-κB activation. Conversely, NF-κB inhibition sensitises ARL-6 cells to H 2 O 2 -induced apoptosis. Sustained NF-κB activation in these HCC cells may protect them against apoptosis produced by oxidative stress.

show abstract

Section: Discussionmentioning

confidence: 97%

NF-κB protects rat ARL-6 hepatocellular carcinoma cells against hydrogen peroxide-induced apoptosis

Qiao¹,

Yu²,

Dent³

et al. 2005

Cancer Biology & Therapy

View full text Add to dashboard Cite

show abstract

“…In addition, NF-κB nuclear translocation was significantly higher in patients with HCC exhibiting adverse clinical features including advanced staging, portal vein tumor thrombus, and the involvement of regional lymph nodes compared with other patients with early-stage disease. Chemotherapeutic agents and radiation are able to trigger the NF-κB-modulated expression of angiogenesis-and metastasis-associated proteins in HCC cells via the activation of NF-κB signaling (15,16). Sorafenib, a multiple kinase inhibitor, has been approved by the FDA for the treatment of advanced HCC (13).…”

Section: Discussionmentioning

confidence: 99%

“…NF-κB was revealed to be more highly expressed in the nucleoli of HCC cells compared with normal hepatic tissue, which was associated with poor prognoses (14). However, a number of Regorafenib diminishes the expression and secretion of angiogenesis and metastasis associated proteins and inhibits cell invasion via NF-κB inactivation in SK-Hep1 cells therapeutic agents, and radiation, induce apoptosis signal and trigger NF-κB activity in HCC in vitro and in vivo (13,15,16). Therefore, the development of novel inhibitors of NF-κB signaling may be useful for preventing angiogenesis and metastasis in patients with HCC.…”

Section: Introductionmentioning

confidence: 99%

Regorafenib diminishes the expression and secretion of angiogenesis and metastasis associated proteins and inhibits cell invasion via NF-κB inactivation in SK-Hep1 cells

Liu

Wang³

2017

Oncology Letters

View full text Add to dashboard Cite

Abstract. The aim of the present study was to investigate the effects of regorafenib on the nuclear factor κ-light-chain-enhancer of activated B cells (NF)-κB-modulated expression of angiogenesis-and metastasis-associated proteins and cell invasion in human hepatocellular carcinoma SK-Hep1 cells. The SK-Hep1 cells were treated with different concentrations of NF-κB inhibitor 4-N-[2-(4-phenoxyphenyl) ethyl] quinazoline-4,6-diamine (QNZ) or regorafenib for 24 or 48 h. The effects of QNZ and regorafenib on cell viability, NF-κB activation, expression and secretion levels of angiogenesis-and metastasis-associated proteins and cell invasion were evaluated with MTT assays, western blotting, ELISA, gelatin zymography and cell invasion assays. The results demonstrated that QNZ and regorafenib significantly reduced the expression and secretion levels of the angiogenesis-and metastasis-associated proteins vascular endothelial growth factor, tumor necrosis factor-α, interleukin (IL)-1β, IL-6, matrix metalloproteinase (MMP)-2 and MMP-9, NF-κB activation and cell invasion. In conclusion, the inhibition of NF-κB activation induces anti-angiogenic and antimetastatic effects in SK-Hep1 cells. Regorafenib reduces the level of expression and secretion of angiogenesis-and metastasis-associated proteins and cell invasion through the suppression of NF-κB activation in SK-Hep1 cells.

show abstract

“…Dox has been shown to activate NFB in a number of cell types (43)(44)(45)(46). Because NFB is also implicated in the transcriptional regulation of CD95 (32, 47, 48), we next analyzed whether NFB was also involved in the Dox-mediated activation of CD95 in HUVECs.…”

Section: P53 Regulates Cd95 Expression and Apoptosis In Huvecsmentioning

confidence: 99%

Doxorubicin Induces Apoptosis and CD95 Gene Expression in Human Primary Endothelial Cells through a p53-dependent Mechanism

Lorenzo

Ruiz‐Ruiz

Quesada

et al. 2002

Journal of Biological Chemistry

142

View full text Add to dashboard Cite

Regulation of the homeostasis of vascular endothelium is critical for the processes of vascular remodeling and angiogenesis under physiological and pathological conditions. Here we show that doxorubicin (Dox), a drug used in antitumor therapy, triggered a marked accumulation of p53 and induced CD95 gene expression and apoptosis in proliferating human umbilical vein endothelial cells (HUVECs). Transfection and site-directed mutagenesis experiments using the CD95 promoter fused to an intronic enhancer indicated the requirement for a p53 site for Dox-induced promoter activation. Furthermore, the p53 inhibitor pifithrin-␣ (PFT-␣) blocked both promoter inducibility and protein up-regulation of CD95 in response to Dox. Up-regulated CD95 in Doxtreated cells was functional in eliciting apoptosis upon incubation of the cells with an agonistic CD95 antibody. However, Dox-mediated apoptosis was independent of CD95/CD95L interaction. The analysis of apoptosis in the presence of PFT-␣ and benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethylketone revealed that both p53 and caspase activation are required for Dox-mediated apoptosis of HUVECs. Finally, Dox triggered Bcl-2 downregulation, cytochrome c release from mitochondria, and the activation of caspases 9 and 3, suggesting the involvement of a mitochondrially operated pathway of apoptosis. These results highlight the role of p53 in the response of primary endothelial cells to genotoxic drugs and may reveal a novel mechanism underlying the antitumoral properties of Dox, related to its ability to induce apoptosis in proliferating endothelial cells.

show abstract

IκBα gene therapy in tumor necrosis factor-α- and chemotherapy-mediated apoptosis of hepatocellular carcinomas

Cited by 18 publications

References 28 publications

NF-κB protects rat ARL-6 hepatocellular carcinoma cells against hydrogen peroxide-induced apoptosis

NF-κB protects rat ARL-6 hepatocellular carcinoma cells against hydrogen peroxide-induced apoptosis

Regorafenib diminishes the expression and secretion of angiogenesis and metastasis associated proteins and inhibits cell invasion via NF-κB inactivation in SK-Hep1 cells

Doxorubicin Induces Apoptosis and CD95 Gene Expression in Human Primary Endothelial Cells through a p53-dependent Mechanism

Contact Info

Product

Resources

About