Repression of BIRC5/Survivin by FOXO3/FKHRL1 Sensitizes Human Neuroblastoma Cells to DNA Damage-induced Apoptosis

Obexer, Petra; Hagenbuchner, Judith; Unterkircher, Thomas; Sachsenmaier, Nora; Seifarth, Christoph; Böck, Günther; Porto, Verena; Geiger, Kathrin; Ausserlechner, Michael J.

doi:10.1091/mbc.e08-07-0699

Cited by 71 publications

(77 citation statements)

References 24 publications

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“…In this paper we further demonstrated that low-level activation of FOXO3 sensitized neuroblastoma cells to the DNA-damaging agents doxorubicin and etoposide, whereas the overexpression of Survivin diminished FOXO3-sensitization to these drugs. These results suggest that repression of Survivin by FOXO3 facilitates FOXO3-induced apoptosis and sensitizes neuroblastoma cells to apoptosis induced by DNAdamaging agents, which supports the central role of PI3K-PKB-FOXO3 signaling in drug resistance of human neuroblastoma (Obexer et al, 2009). As FOXO3 induction seems to be beneficial for the treatment in neuroblastoma, we searched for natural compounds that might activate FOXO3.…”

Section: Foxo3 In Neuroblastoma Cellssupporting

confidence: 69%

“…In neuroblastoma the expression of Survivin has been reported to correlate with a reduced apoptotic index in vivo, with a shortened overall survival rate, an unfavorable prognosis and an increased relapse rate. We have shown that FOXO3 is an upstream regulator of Survivin in neuroblastoma and that Survivin is critical for sensitivity to chemotherapeutic agents (Obexer et al, 2009). …”

Section: Foxo3 Represses Immune Function and Immune Surveillancementioning

confidence: 99%

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FOXO Transcription Factors as Potential Therapeutic Targets in Neuroblastoma

Ausserlechner¹,

Hagenbuchner²,

Fuchs³

et al. 2012

Neuroblastoma - Present and Future

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Section: Foxo3 In Neuroblastoma Cellssupporting

confidence: 69%

Section: Foxo3 Represses Immune Function and Immune Surveillancementioning

confidence: 99%

FOXO Transcription Factors as Potential Therapeutic Targets in Neuroblastoma

Ausserlechner¹,

Hagenbuchner²,

Fuchs³

et al. 2012

Neuroblastoma - Present and Future

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“…This protein is an essential regulator of cell division (Connell et al, 2008), a modulator of apoptotic and nonapoptotic cell death and a stress response factor ensuring continued cell proliferation and cell survival in the face of unfavourable milieus (Altieri, 2005). Survivin antagonizes apoptosis (Obexer et al, 2009), promotes tumour-associated angiogenesis (Zhen et al, 2007) and acts as a resistance factor to various anticancer therapies (Wu et al, 2008). Although there are disparate and seemingly distant fields of investigation, only a holistic understanding of survivin function across the different areas can unlock the potential of the survivin networks for novel cancer therapeutics.…”

Section: Introductionmentioning

confidence: 99%

The transcription factor GATA-1 is overexpressed in breast carcinomas and contributes to survivin upregulation via a promoter polymorphism

et al. 2010

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Expression of survivin, a member of the inhibitor of apoptosis protein family, is elevated in human cancers and considered as a new therapeutic target. Mechanism upregulating survivin expression in tumour cells is poorly understood. In this study, we show that breast cancer patients harbouring a polymorphism G235A in the survivin promoter present a higher level of survivin expression. This polymorphism creates a binding site for the transcription factor GATA-1 inducing a second GATA-1-binding site in survivin promoter. At the mRNA level, GATA-1 was present in breast carcinomas and adjacent normal tissues, whereas the protein was only detected in carcinomas by western blot and immunohistochemistry. Transfection of wild-type and different constitutively active GATA-1 mutants (serine 26, 178 or 310) showed that only phospho-serine 26 GATA-1 was able to increase survivin expression. This increase was higher in G235A than in G235G cell lines. Phospho-serine 26 GATA-1 bound directly survivin promoter, with a stronger interaction in G235A than in G235G polymorphism indicating that both GATA-1-binding sites are functional. These data identify GATA-1 as a key feature in tumour aggressiveness by enhancing survivin expression and delineate its targeting as a possible new therapeutic strategy in breast carcinomas.

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“…Functional roles of this protein include being a regulator of cell division (34), a modulator of both apoptotic and nonapoptotic cell death, as well as a stress response factor to ensure continued cell proliferation and survival when faced with adverse environments (35). Additionally, survivin is known to antagonize angiogenesis (36) and act as a factor in resistance to a variety of anticancer therapies (37). Interestingly, high survivin expression is reported in ovarian carcinomas and this has been observed to be associated with higher clinical stage, lymph node metastasis, poorer differentiation grade, and therefore may potentially serve as a prognostic marker for patients with ovarian cancer because the levels of survivin were highest in ovarian carcinomas and lowest in benign ovarian masses (38).…”

Section: Discussionmentioning

confidence: 99%