Partial Beclin 1 silencing aggravates doxorubicin- and Fas-induced apoptosis in HepG2 cells

Daniel, Fanny; Legrand, Agnès; Pessayre, Dominique; Vadrot, Nathalie; Descatoire, Véronique; Bernuau, Dominique

doi:10.3748/wjg.v12.i18.2895

Cited by 32 publications

(37 citation statements)

References 25 publications

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“…Furthermore, the relative levels of cyclin d1, cdK4, Bcl-2 and Bcl-xl in Beclin 1-silenced cells were also comparable to those in control cells, accompanied by very low levels of active caspase-3 in both groups of cells. These data are consistent with previously reported results (19), and indicate that the knockdown of Beclin 1 expression did not significantly affect hepatoma cell proliferation and spontaneous apoptosis. However, our data were in disagreement with the finding that the partial downregulation of Beclin 1 expression augmented the apoptosis of HepG2 cells in vitro (19).…”

Section: Discussionsupporting

confidence: 94%

“…These data are consistent with previously reported results (19), and indicate that the knockdown of Beclin 1 expression did not significantly affect hepatoma cell proliferation and spontaneous apoptosis. However, our data were in disagreement with the finding that the partial downregulation of Beclin 1 expression augmented the apoptosis of HepG2 cells in vitro (19). This difference may be due to the use of different hepatoma cell lines or different experimental conditions.…”

Section: Discussionsupporting

confidence: 94%

“…We examined the impact of Beclin 1 knockdown on VK 3 -mediated growth inhibition, apoptosis and autophagy in human hepatoma cells, and found that treatment with VK 3 significantly inhibited the growth of SMMC-7721 cells and triggered a high frequency of hepatoma cell apoptosis in vitro, accompanied by high levels of caspase-3 activation. indeed, VK 3 augments doxorubicin-and Fas-induced apoptosis in hepatoma-derived HepG2 cells (19). These regulatory effects of VK 3 were likely mediated by the inhibition of the expression of cyclin d1, cdK4, Bcl-2 and Bcl-xl in SMMc-7721 cells, similar to previous reports using other human hepatoma cell lines (4)(5)(6)(7)19).…”

Section: Discussionsupporting

confidence: 86%

“…Beclin 1 is an upstream critical regulator of various autophagy signaling pathways, and is responsible for mediating the formation of aVs (18). Moreover, the knockdown of Beclin 1 expression enhances Fas-induced apoptosis and doxorubicin-mediated aggravating mitochondrial permeabilization in HepG2 cells in vitro (19), while the overexpression of Beclin 1 augments the cis-diamminedichloroplatinum-induced apoptosis of gastric cancer MKn28 cells by enhancing caspase-9 activity (20). Therefore, Beclin 1 is a dual functional regulator of autophagy and apoptosis.…”

Section: Introductionmentioning

confidence: 98%

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Knockdown of Beclin 1 inhibits vitamin K3‑induced autophagy, but promotes apoptosis of human hepatoma SMMC-7721 cells

Yang

Han

2010

Mol Med Rep

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Abstract. The aim of the present study was to investigate the effects of Beclin 1 knockdown on spontaneous and vitamin K 3 (VK 3 )-regulated autophagy, survival and apoptosis in human hepatocarcinoma SMMc-7721 cells, and to explore the potential mechanisms underlying the action of Beclin 1 knockdown in the processes of autophagy and apoptosis. a recombinant plasmid-expressing small interfering rna (sirna) targeting Beclin 1 mrna was constructed and introduced into SMMc-7721 cells. The expression of Beclin 1 was determined by reverse transcription-polymerase chain reaction and Western blotting. Subsequently, the impact of Beclin 1 knockdown on spontaneous and VK 3 -induced autophagy, survival and apoptosis was determined. The expression of cyclin d1, cyclindependent kinase 4 (cdK4), Bcl-2, Bcl-xl and the activation of caspase-3 were examined by Western blotting. Transfection with the plasmid for Beclin 1 sirna expression dramatically down-regulated Beclin 1 expression in SMMc-7721 cells. The knockdown of Beclin 1 expression significantly inhibited spontaneous and VK 3 -induced autophagy, but did not affect spontaneous proliferation and apoptosis in SMMc-7721 cells in vitro. By contrast, the silencing of Beclin 1 expression significantly enhanced the inhibition of survival and proliferation by VK 3 , and promoted VK 3 -induced apoptosis by significantly down-regulating cyclin D1, CDK4, Bcl-2 and Bcl-xl expression and enhancing caspase-3 activation in SMMc-7721 cells in vitro. our data indicate that Beclin 1 is a positive regulator of autophagy, but a negative regulator of VK 3 -induced apoptosis in human hepatoma cells.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 98%

See 2 more Smart Citations

Knockdown of Beclin 1 inhibits vitamin K3‑induced autophagy, but promotes apoptosis of human hepatoma SMMC-7721 cells

Yang

Han

2010

Mol Med Rep

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“…A number of emerging pieces of evidence point to a prosurvival role for autophagy. Inactivation of the essential autophagy gene BECN1 results in apoptotic cell death in different models (8,11,55). Autophagy has been shown to represent a temporary survival pathway that counteracts metabolic stress in tumors with defective apoptosis, and it is required for the maintenance of energy homeostasis in healthy cells during postnatal starvation (29).…”

mentioning

confidence: 99%

p65/RelA Modulates BECN1 Transcription and Autophagy

Copetti

Bertoli

Dalla

et al. 2009

Molecular and Cellular Biology

235

179

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Recently, autophagy has emerged as a critical process in the control of T-cell homeostasis. Given the pivotal role of NF-B in the signaling events of T cells, we have analyzed and unveiled a conserved NF-B binding site in the promoter of the murine and human BECN1 autophagic gene (Atg6). Accordingly, we demonstrate that the NF-B family member p65/RelA upregulates BECN1 mRNA and protein levels in different cellular systems. Moreover, p65-mediated upregulation of BECN1 is coupled to increased autophagy. The newly identified B site in the BECN1 promoter specifically interacts with p65 both in vitro and in living Jurkat cells upon phorbol myristate acetate (PMA)-ionomycin stimulation, where p65 induction is coupled to BECN1 upregulation and autophagy induction. Finally, anti-CD3-and PMA-ionomycin-mediated activation of T-cell receptor signaling in peripheral T cells from lymph nodes of healthy mice results in an upregulation of BECN1 expression that can be blocked by the NF-B inhibitor BAY 11-7082. Altogether, these data suggest that autophagy could represent a novel route modulated by p65 to regulate cell survival and control T-cell homeostasis.Normal cellular development and growth depend on a finely tuned balance between protein synthesis and degradation. Eukaryotic cells exploit two major routes for protein degradation: autophagy and the ubiquitin-proteasome system. Autophagy is a highly conserved catabolic process whereby long-lived proteins and organelles are engulfed in double-membrane structures called autophagosomes and targeted to the lysosome for degradation and ATP production (33). Autophagy was first characterized in yeast as a process used by cells to survive metabolic stress (59). Many of the autophagic executor genes (ATGs) have been discovered in yeast, and recently a number of mammalian orthologues have been identified. At the molecular level, the autophagic pathway is well conserved and requires several proteins acting in concert at different stages for proper autophagosome formation. During the first steps of autophagosome formation, BECN1/Atg6 acts in association with PI3KIII/Vps34 as a platform that recruits activators and inhibitors of autophagy in order to finely regulate autophagosome formation (43). Two ubiquitin-like systems are fundamental for autophagosome enlargement and maturation downstream of BECN1. A first ubiquitin-like system is required for the formation of the Atg5-Atg12 complex, which contributes to autophagosomal membrane elongation (30, 39). The second ubiquitin-like system conjugates LC3 protein to phosphoethanolamine, allowing its incorporation into the autophagosomal membrane and subsequent autophagosome formation (56).In mammalian cells, metabolic stress and genotoxic stimuli, including ceramide and tamoxifen treatment, have been shown to trigger both apoptotic cell death and autophagy (51). A number of emerging pieces of evidence point to a prosurvival role for autophagy. Inactivation of the essential autophagy gene BECN1 results in apoptotic cell death in different mode...

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A potential estrogen mimetic effect of a bis(ethyl)polyamine analogue on estrogen receptor positive MCF-7 breast cancer cells

et al. 2011

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BE-3-3-3-3 (1,15-(ethylamino)4,8,12-triazapentadecane) is a bis(ethyl)polyamine analogue under investigation as a therapeutic agent for breast cancer. Since estradiol (E(2)) is a critical regulatory molecule in the growth of breast cancer, we examined the effect of BE-3-3-3-3 on estrogen receptor α (ERα) positive MCF-7 cells in the presence and absence of E(2). In the presence of E(2), a concentration-dependent decrease in DNA synthesis was observed using [(3)H]-thymidine incorporation assay. In the absence of E(2), low concentrations (2.5-10 μM) of BE-3-3-3-3 increased [(3)H]-thymidine incorporation at 24 and 48 h. BE-3-3-3-3 induced the expression of early response genes, c-myc and c-fos, in the absence of E(2), but not in its presence, as determined by real-time quantitative polymerase chain reaction (qPCR). BE-3-3-3-3 had no significant effect on these genes in an ERα-negative cell line, MDA-MB-231. Chromatin immunoprecipitation assay demonstrated enhanced promoter occupation by either E(2) or BE-3-3-3-3 of an estrogen-responsive gene pS2/Tff1 by ERα and its co-activator, steroid receptor co-activator 3 (SRC-3). Confocal microscopy of BE-3-3-3-3-treated cells revealed membrane localization of ERα, similar to that induced by E(2). The failure of BE-3-3-3-3 to inhibit cell proliferation was associated with autophagic vacuole formation, and the induction of Beclin 1 and MAP LC3 II. These results indicate a differential effect of BE-3-3-3-3 on MCF-7 cells in the absence and presence of E(2), and suggest that pre-clinical and clinical development of polyamine analogues might require special precautions and selection of sensitive subpopulation of patients.

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Partial Beclin 1 silencing aggravates doxorubicin- and Fas-induced apoptosis in HepG2 cells

Abstract: Partial Beclin 1 silencing aggravates mitochondrial permeabilization and apoptosis in HepG2 cells treated with an anti-Fas antibody or with doxorubicin.

Cited by 32 publications

References 25 publications

Knockdown of Beclin 1 inhibits vitamin K3‑induced autophagy, but promotes apoptosis of human hepatoma SMMC-7721 cells

Knockdown of Beclin 1 inhibits vitamin K3‑induced autophagy, but promotes apoptosis of human hepatoma SMMC-7721 cells

p65/RelA Modulates BECN1 Transcription and Autophagy

A potential estrogen mimetic effect of a bis(ethyl)polyamine analogue on estrogen receptor positive MCF-7 breast cancer cells

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