Simultaneous inhibition of mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways augment the sensitivity to actinomycin D in Ewing sarcoma

Yamamoto, Tomohisa; Ohno, Takatoshi; Wakahara, Kazuhiko; Nagano, Akihito; Kawai, Gou; Saitou, Mitsuru; Takigami, Iori; Matsuhashi, Aya; Yamada, Kazunari; Shimizu, Katsuji

doi:10.1007/s00432-009-0554-z

Cited by 21 publications

(22 citation statements)

References 39 publications

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“…PRAS40 also plays an important role in cell survival among different species (20). PRAS40 promotes the tumorigenesis of melanoma by deregulating apoptosis (30). Our results are consistent with these observations.…”

Section: Discussionsupporting

confidence: 91%

“…PI3K inhibitors augment apoptosis in ESFT cells induced by drugs now clinically used to treat Ewing sarcoma: actinomycin D (30) and doxorubicin (31). To clarify whether the PI3K/Akt inhibitors influence the proliferation of ESFT cells, we treated A673 cells with a PI3K inhibitor, LY294002 or Wortmannin, or an Akt inhibitor, API-2 (triciribine).…”

Section: Pi3k/akt Inhibitors Suppress the Growth Of Esft Cellsmentioning

confidence: 99%

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PRAS40 Is a Functionally Critical Target for EWS Repression in Ewing Sarcoma

Huang

Nakai²,

Kuwahara³

et al. 2012

Cancer Research

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Ewing sarcoma family tumors (ESFT) are highly aggressive and highly metastatic tumors caused by a chromosomal fusion between the Ewing sarcoma protein (EWS) with the transcription factor FLI-1. However, expression of the EWS/FLI-1 chimeric oncogene by itself is insufficient for carcinogenesis, suggesting that additional events are required. Here, we report the identification of the Akt substrate PRAS40 as an EWS target gene. EWS negatively regulates PRAS40 expression by binding the 3 0 untranslated region in PRAS40 mRNA. ESFT cell proliferation was suppressed by treatment with an Akt inhibitor, and ESFT cell proliferation and metastatic growth were suppressed by siRNA-mediated PRAS40 knockdown. Furthermore, PRAS40 knockdown was sufficient to reverse an increased cell proliferation elicited by EWS knockdown. In support of a pathologic role for PRAS40 elevation in EFST, we documented inverse protein levels of EWS and PRAS40 in ESFT cells. Together, our findings suggest that PRAS40 promotes the development of ESFT and might therefore represent a novel therapeutic target in this aggressive disease. Cancer Res; 72(5);

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Section: Discussionsupporting

confidence: 91%

Section: Pi3k/akt Inhibitors Suppress the Growth Of Esft Cellsmentioning

confidence: 99%

PRAS40 Is a Functionally Critical Target for EWS Repression in Ewing Sarcoma

Huang

Nakai²,

Kuwahara³

et al. 2012

Cancer Research

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“…Western blot analyses were carried out as described previously (47,48). The following antibodies were used: anti-HA (rabbit IgG, 1:1,000 dilution; Cell Signaling), anti-Fos (rabbit IgG, 1:1,000 dilution; Cell Signaling), anti-ERK1/2 (rabbit IgG, 1:1,000 dilution; Cell Signaling), anti-phospho-ERK1/2 (rabbit IgG, 1:1,000 dilution; Cell Signaling), anti-ATF1 (rabbit IgG, 1:5,000 dilution; EPITOMICS), and anti-β-actin (mouse IgG, 1:5,000 dilution; Calbiochem).…”

Section: Molecular Cloning and Gene Targeting In Es Cells Human Ews/mentioning

confidence: 99%

EWS/ATF1 expression induces sarcomas from neural crest–derived cells in mice

Yamada¹,

Ohno²,

Aoki³

et al. 2013

J. Clin. Invest.

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Clear cell sarcoma (CCS) is an aggressive soft tissue malignant tumor characterized by a unique t(12;22) translocation that leads to the expression of a chimeric EWS/ATF1 fusion gene. However, little is known about the mechanisms underlying the involvement of EWS/ATF1 in CCS development. In addition, the cellular origins of CCS have not been determined. Here, we generated EWS/ATF1-inducible mice and examined the effects of EWS/ATF1 expression in adult somatic cells. We found that forced expression of EWS/ATF1 resulted in the development of EWS/ATF1-dependent sarcomas in mice. The histology of EWS/ATF1-induced sarcomas resembled that of CCS, and EWS/ATF1-induced tumor cells expressed CCS markers, including S100, SOX10, and MITF. Lineage-tracing experiments indicated that neural crest-derived cells were subject to EWS/ATF1-driven transformation. EWS/ATF1 directly induced Fos in an ERK-independent manner. Treatment of human and EWS/ATF1-induced CCS tumor cells with FOS-targeted siRNA attenuated proliferation. These findings demonstrated that FOS mediates the growth of EWS/ATF1-associated sarcomas and suggest that FOS is a potential therapeutic target in human CCS.

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“…Ainsi, Yamamoto et al ont obtenu une augmentation de l'effet antitumoral de l'actinomycine D dans des cellules du sarcome d'Ewing in vitro en inhibant EWS/ FLi-1 par un siARN [38].…”

Section: Culture Cellulaireunclassified

Vers une thérapeutique ciblée du sarcome d’Ewing par une stratégie antisens

Ramon

Malvy

2009

Oncologie

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The Ewing sarcoma family of tumors is characterized by a translocation between chromosomes 11 and 22. This creates a rearranged chromosome 22 containing a chimeric oncogene: EWS/ Fli-1. The EWS/Fli-1 protein plays an important role in the transformation of Ewing cells. The fusion region at the mRNA level coding for EWS/Fli-1 is a specific target for antisense strategies. It is indeed present only in cancer cells. We describe the in vitro and in vivo results obtained according to this idea first with antisense oligonucleotides and then with siRNAs. Finally prospects for clinical applications with antisense molecules are discussed.

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Simultaneous inhibition of mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways augment the sensitivity to actinomycin D in Ewing sarcoma

Cited by 21 publications

References 39 publications

PRAS40 Is a Functionally Critical Target for EWS Repression in Ewing Sarcoma

PRAS40 Is a Functionally Critical Target for EWS Repression in Ewing Sarcoma

EWS/ATF1 expression induces sarcomas from neural crest–derived cells in mice

Vers une thérapeutique ciblée du sarcome d’Ewing par une stratégie antisens

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