bcl-2 over-expression enhances NF-κB activity and induces mmp-9 transcription in human MCF7ADR breast-cancer cells

Ricca, Alfredo; Biroccio, Annamaria; Bufalo, Donatella Del; Mackay, Andrew R.; Santoni, Angela; Cippitelli, Marco

doi:10.1002/(sici)1097-0215(20000415)86:2<188::aid-ijc7>3.3.co;2-n

Cited by 29 publications

(54 citation statements)

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“…4,5,[29][30][31][32][33] Moreover, some bcl-2 protein interactors, such as the bcl-2 mitochondrial chaperone FKBP38, the orphan nuclear receptor Nur77 and the molecular chaperone HSP90, have been demonstrated to be involved in oxygen-dependent and -independent regulation of the HIF-1a protein. [33][34][35] Even if we recently demonstrated that bcl-2 protein under hypoxic conditions interacts with both HIF-1a and HSP90 proteins contributing to the enhancement of HIF-1a protein stability, 21 we cannot exclude that also other bcl-2 interactors can be involved in bcl-2-induced HIF-1a/VEGF regulation.…”

Section: Discussionsupporting

confidence: 55%

“…The BH4 domain is necessary and sufficient for bcl-2 to prevent apoptosis, bind to bax, translocate into the nucleus, (a-g) TAT-CTRL (control peptide), TAT-BH4 (peptide corresponding to wild-type BH4 domain of bcl-2) and TAT-BH4mut (peptide corresponding to a mutated versions of BH4 domain into amino acids 6-7) were used reduce cell proliferation, induce nuclear factor-kappa B activity and regulate DNA repair. 4,5,28 In addition, some authors have suggested that bcl-2 deleted of its BH4 domain functions like bax to promote, rather than inhibit, cell death, 6 while other groups have reported that BH4 deletion converts bcl-2 into a dominant-negative inhibitor of bcl-2. 7 In our experimental model, the bcl-2 protein deleted of BH4 domain did not function as a dominant-negative inhibitor toward the bcl-2 ability to protect from apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…The amino-terminal BH4 domain is mainly found in the bcl-2 family members with death-repressing activity, 1 but it is also present in some proapoptotic molecules. 2 BH4 domain of bcl-2 and bcl-xL is critical for interaction with and/or regulation of several proteins involved in apoptosis [3][4][5][6] and all BH domains are necessary for the antiapoptotic function of bcl-2 and bcl-xL. 7 In addition to protecting from apoptosis and increasing survival, bcl-2 and bcl-xL are involved in several other important functions, including angiogenesis.…”

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confidence: 99%

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Involvement of BH4 domain of bcl-2 in the regulation of HIF-1-mediated VEGF expression in hypoxic tumor cells

Trisciuoglio¹,

Gabellini

Desideri³

et al. 2011

Cell Death Differ

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In addition to act as an antiapoptotic protein, B-cell lymphoma (bcl)-2 can also promote tumor angiogenesis. In this context, we have previously demonstrated that under hypoxia bcl-2 promotes hypoxia-inducible factor-1 (HIF-1)-mediated vascular endothelial growth factor (VEGF) expression in melanoma and breast carcinoma. Here, we report on the role of the BH4 domain in bcl-2 functions, by showing that removal of or mutations at the BH4 domain abrogate the ability of bcl-2 to induce VEGF protein expression and transcriptional activity under hypoxia in human melanoma cells. We have also extended this observation to other human tumor histotypes, such as colon, ovarian and lung carcinomas. The involvement of BH4 on HIF-1a protein expression, stability, ubiquitination and HIF-1 transcriptional activity was also demonstrated in melanoma experimental model. Moreover, we validated the role of the BH4 domain of bcl-2 in the regulation of HIF-1/VEGF axis, demonstrating that BH4 peptide is sufficient to increase HIF-1a protein half-life impairing HIF-1a protein ubiquitination, and to enhance VEGF secretion in melanoma cells exposed to hypoxia. Finally, we found that the mechanism by which bcl-2 regulates HIF-1-mediated VEGF expression does not require BH1 and BH2 domains, and it is independent of antiapoptotic and prosurvival function of bcl-2.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Involvement of BH4 domain of bcl-2 in the regulation of HIF-1-mediated VEGF expression in hypoxic tumor cells

Trisciuoglio¹,

Gabellini

Desideri³

et al. 2011

Cell Death Differ

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“…Moreover, Bcl-2 regulates gene expression and modulates the transactivity of several transcription factors (Feng Ricca et al, 2000;Schwarz et al, 2002;Cory et al, 2003;Quinn and Richardson, 2004).…”

Section: Discussionmentioning

confidence: 99%

Involvement of PI3K and MAPK Signaling in bcl-2-induced Vascular Endothelial Growth Factor Expression in Melanoma Cells

Trisciuoglio¹,

Iervolino²,

Zupi³

et al. 2005

MBoC

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We have previously demonstrated that bcl-2 overexpression in tumor cells exposed to hypoxia increases the expression of vascular endothelial growth factor (VEGF) gene through the hypoxia-inducible factor-1 (HIF-1). In this article, we demonstrate that exposure of bcl-2 overexpressing melanoma cells to hypoxia induced phosphorylation of AKT and extracellular signal-regulated kinase (ERK)1/2 proteins. On the contrary, no modulation of these pathways by bcl-2 was observed under normoxic conditions. When HIF-1␣ expression was reduced by RNA interference, AKT and ERK1/2 phosphorylation were still induced by bcl-2. Pharmacological inhibition of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) signaling pathways reduced the induction of VEGF and HIF-1 in response to bcl-2 overexpression in hypoxia. No differences were observed between control and bcl-2-overexpressing cells in normoxia, in terms of VEGF protein secretion and in response to PI3K and MAPK inhibitors. We also demonstrated that RNA interference-mediated down-regulation of bcl-2 expression resulted in a decrease in the ERK1/2 phosphorylation and VEGF secretion only in bcl-2-overexpressing cell exposed to hypoxia but not in control cells. In conclusion, our results indicate, for the first time, that bcl-2 synergizes with hypoxia to promote expression of angiogenesis factors in melanoma cells through both PI3K-and MAPK-dependent pathways. INTRODUCTIONAngiogenesis is a complex and multilevel process of new capillary formation on the basis of already existing blood vessels. Physiologically, it is a very strictly regulated process, which results in a balance between stimulatory (angiogenic) and inhibitory (angiostatic) factors to control the correct development of blood vessels. Angiogenesis is a rate-limiting step in tumor growth and progression, and many tumors develop a severely hypoxic microenvironment and secrete angiogenesis-stimulating factors (Folkman et al., 1971;Talks et al., 2000). Vascular endothelial growth factor (VEGF), a potent and specific mitogen for vascular endothelial cells, is a critical mediator of angiogenesis. Its expression is induced in cancer cells as a result of hypoxia and multiple genetic alterations, including p53 and PTEN loss-of-function, RAS and SRC gain-of-function, and autocrine tyrosine kinase signaling pathways (Mukhopadhyay et al., 1995;Arbiser et al., 1997;Petit et al., 1997;Akagi et al., 1998;Ellis et al., 1998;Yen et al., 2000). Based on the analysis of melanoma and breast cancer cells recently reported by our group Iervolino et al., 2002;Del Bufalo et al., 2003;Trisciuoglio et al., 2004), this list can now be extended to include the increased VEGF expression resulting from bcl-2 overexpression. Hypoxia-and growth factor-induced VEGF expression in tumor cells is regulated by the hypoxia inducible factor 1 (HIF-1) (Jiang et al., 1997;Mazure et al., 1997;Ravi et al., 2000;Zhong et al., 2000;Zundel et al., 2000;Laughner et al., 2001;Fukuda et al., 2002), a transcription factor that is compose...

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“…Since a link of Bcl-2 and the NF-κB signaling pathway has been described for other cell lines [12][13][14][15]32], we examined 1) whether Bcl-2 overexpressing Jurkat cells…”

Section: Role Of Nf-κbmentioning

confidence: 99%

Helenalin bypasses Bcl-2-mediated cell death resistance by inhibiting NF-κB and promoting reactive oxygen species generation

Hoffmann

Schwarzenberg

López-Antón

et al. 2011

Biochemical Pharmacology

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractEvasion of cell death by overexpression of anti-apoptotic proteins, such as Bcl-2, is commonly observed in cancer cells leading to a lack of response to chemotherapy.Hence, there is a need to find new chemotherapeutic agents that are able to overcome chemoresistance mediated by Bcl-2 and to understand their mechanisms of action. Helenalin, a sesquiterpene lactone ( and free intracellular iron as mediators of helenalin-induced cell death whereas activation of JNK and abrogation of Akt activity did not contribute to helenalin-elicited cell death. Our results highlight the NF-κB inhibitor helenalin as a promising chemotherapeutic agent to overcome Bcl-2-induced cell death resistance.

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bcl-2 over-expression enhances NF-κB activity and induces mmp-9 transcription in human MCF7ADR breast-cancer cells

Cited by 29 publications

References 0 publications

Involvement of BH4 domain of bcl-2 in the regulation of HIF-1-mediated VEGF expression in hypoxic tumor cells

Involvement of BH4 domain of bcl-2 in the regulation of HIF-1-mediated VEGF expression in hypoxic tumor cells

Involvement of PI3K and MAPK Signaling in bcl-2-induced Vascular Endothelial Growth Factor Expression in Melanoma Cells

Helenalin bypasses Bcl-2-mediated cell death resistance by inhibiting NF-κB and promoting reactive oxygen species generation

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