The Quassinoid Derivative NBT-272 Targets Both the AKT and ERK Signaling Pathways in Embryonal Tumors

Castelletti, Deborah; Fiaschetti, Giulio; Dato, Valeria Di; Ziegler, Urs; Kumps, Candy; Preter, Katleen De; Zollo, Massimo; Speleman, Franki; Shalaby, Tarek; Martino, Daniela De; Berg, Thorsten; Eggert, Angelika; Arcaro, Alexandre; Grotzer, Michael A.

doi:10.1158/1535-7163.mct-10-0539

Cited by 14 publications

(9 citation statements)

References 48 publications

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“…In embryonal tumors, including medulloblastoma, targeting the AKT and ERK pathways using a quassinoid analogue induced c-Myc and N-myc down-regulation [ 7 , 59 ]. Inhibition of PI3K using a selective inhibitor was also reported to induce N-myc down-regulation in neuroblastoma [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

The Phosphoinositide 3-Kinase p110α Isoform Regulates Leukemia Inhibitory Factor Receptor Expression via c-Myc and miR-125b to Promote Cell Proliferation in Medulloblastoma

et al. 2015

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Medulloblastoma (MB) is the most common malignant brain tumor in childhood and represents the main cause of cancer-related death in this age group. The phosphoinositide 3-kinase (PI3K) pathway has been shown to play an important role in the regulation of medulloblastoma cell survival and proliferation, but the molecular mechanisms and downstream effectors underlying PI3K signaling still remain elusive. The impact of RNA interference (RNAi)-mediated silencing of PI3K isoforms p110α and p110δ on global gene expression was investigated by DNA microarray analysis in medulloblastoma cell lines. A subset of genes with selectively altered expression upon p110α silencing in comparison to silencing of the closely related p110δ isoform was revealed. Among these genes, the leukemia inhibitory factor receptor α (LIFR α) was validated as a novel p110α target in medulloblastoma. A network involving c-Myc and miR-125b was shown to be involved in the control of LIFRα expression downstream of p110α. Targeting the LIFRα by RNAi, or by using neutralizing reagents impaired medulloblastoma cell proliferation in vitro and induced a tumor volume reduction in vivo. An analysis of primary tumors revealed that LIFRα and p110α expression were elevated in the sonic hedgehog (SHH) subgroup of medulloblastoma, indicating its clinical relevance. Together, these data reveal a novel molecular signaling network, in which PI3K isoform p110α controls the expression of LIFRα via c-Myc and miR-125b to promote MB cell proliferation.

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Section: Discussionmentioning

confidence: 99%

The Phosphoinositide 3-Kinase p110α Isoform Regulates Leukemia Inhibitory Factor Receptor Expression via c-Myc and miR-125b to Promote Cell Proliferation in Medulloblastoma

et al. 2015

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“…Intriguingly, the subgroup of MB characterized by activated SHH signalling is perhaps the one in which most targets have been described so far. The direct targeting of c-Myc in MB has been described by various approaches, including RNAi and pharmacological approaches [ 29 , 30 , 31 ]. In addition, it has been reported that interfering with signalling pathways controlled by c-Myc can impair MB cell proliferation [ 11 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

RNA interference screening identifies a novel role for PCTK1/CDK16 in medulloblastoma with c-Myc amplification

et al. 2014

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Medulloblastoma (MB) is the most common malignant brain tumor in children and is associated with a poor outcome. cMYC amplification characterizes a subgroup of MB with very poor prognosis. However, there exist so far no targeted therapies for the subgroup of MB with cMYC amplification. Here we used kinome-wide RNA interference screening to identify novel kinases that may be targeted to inhibit the proliferation of c-Myc-overexpressing MB. The RNAi screen identified a set of 5 genes that could be targeted to selectively impair the proliferation of c-Myc-overexpressing MB cell lines: AKAP12 (A-kinase anchor protein), CSNK1α1 (casein kinase 1, alpha 1), EPHA7 (EPH receptor A7) and PCTK1 (PCTAIRE protein kinase 1). When using RNAi and a pharmacological inhibitor selective for PCTK1, we could show that this kinase plays a crucial role in the proliferation of MB cell lines and the activation of the mammalian target of rapamycin (mTOR) pathway. In addition, pharmacological PCTK1 inhibition reduced the expression levels of c-Myc. Finally, targeting PCTK1 selectively impaired the tumor growth of c-Myc-overexpressing MB cells in vivo. Together our data uncover a novel and crucial role for PCTK1 in the proliferation and survival of MB characterized by cMYC amplification.

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“…DAOY medulloblastoma cells were transfected with a 96-well plate arrayed library of siRNA duplexes targeting each of the 719 human kinase genes. We chose the DAOY cell line for the screen, as well as UW-228 and PFSK cell lines for validation experiments, because our previous published work has characterized these cell lines in terms of response to cisplatin and activation of various survival pathways (11,19,(22)(23)(24). The characteristics of the cell lines under study are described in the Supplementary Table S1.…”

Section: Identification Of Protein and Lipid Kinases Involved In Medumentioning

confidence: 99%

A Sensitized RNA Interference Screen Identifies a Novel Role for the PI3K p110γ Isoform in Medulloblastoma Cell Proliferation and Chemoresistance

Guerreiro

Fattet

Kulesza

et al. 2011

Molecular Cancer Research

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Medulloblastoma is the most common malignant brain tumor in children and is associated with a poor outcome. We were interested in gaining further insight into the potential of targeting the human kinome as a novel approach to sensitize medulloblastoma to chemotherapeutic agents. A library of small interfering RNA (siRNA) was used to downregulate the known human protein and lipid kinases in medulloblastoma cell lines. The analysis of cell proliferation, in the presence or absence of a low dose of cisplatin after siRNA transfection, identified new protein and lipid kinases involved in medulloblastoma chemoresistance. PLK1 (polo-like kinase 1) was identified as a kinase involved in proliferation in medulloblastoma cell lines. Moreover, a set of 6 genes comprising ATR, LYK5, MPP2, PIK3CG, PIK4CA, and WNK4 were identified as contributing to both cell proliferation and resistance to cisplatin treatment in medulloblastoma cells. An analysis of the expression of the 6 target genes in primary medulloblastoma tumor samples and cell lines revealed overexpression of LYK5 and PIK3CG. The results of the siRNA screen were validated by target inhibition with specific pharmacological inhibitors. A pharmacological inhibitor of p110g (encoded by PIK3CG) impaired cell proliferation in medulloblastoma cell lines and sensitized the cells to cisplatin treatment. Together, our data show that the p110g phosphoinositide 3-kinase isoform is a novel target for combinatorial therapies in medulloblastoma. Mol Cancer Res; 9(7); 925-35. '2011 AACR.

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The Quassinoid Derivative NBT-272 Targets Both the AKT and ERK Signaling Pathways in Embryonal Tumors

Cited by 14 publications

References 48 publications

The Phosphoinositide 3-Kinase p110α Isoform Regulates Leukemia Inhibitory Factor Receptor Expression via c-Myc and miR-125b to Promote Cell Proliferation in Medulloblastoma

The Phosphoinositide 3-Kinase p110α Isoform Regulates Leukemia Inhibitory Factor Receptor Expression via c-Myc and miR-125b to Promote Cell Proliferation in Medulloblastoma

RNA interference screening identifies a novel role for PCTK1/CDK16 in medulloblastoma with c-Myc amplification

A Sensitized RNA Interference Screen Identifies a Novel Role for the PI3K p110γ Isoform in Medulloblastoma Cell Proliferation and Chemoresistance

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