Identification of a Novel Raf-1 Pathway Activator that Inhibits Gastrointestinal Carcinoid Cell Growth

Cook, Mackenzie R.; Pinchot, Scott N.; Jaskula-Sztul, Renata; Luo, Jie; Kunnimalaiyaan, Muthusamy; Chen, Herbert

doi:10.1158/1535-7163.mct-09-0718

Cited by 31 publications

(59 citation statements)

References 40 publications

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“…By contrast, it has been reported that RAF1 activation led to a significant decrease in secretion from medullary thyroid carcinoma cells (decrease of CgA and calcitonin), human pancreatic (BON) and human pulmonary (H727) NET cells (Sippel & Chen 2002, Sippel et al . 2003 a , b , Cook et al . 2010).…”

Section: Discussionmentioning

confidence: 99%

“…(2003 b ) found that RAF1 activation did not to influence human pancreatic (BON) NET cell growth, other studies suggested that the RAF1 activator ZM336372 (as well as the drugs leflunomide and teriflunomide – both also associated with RAF1 pathway activation) suppressed the growth of human pulmonary (H727) and human pancreatic (BON) NET cells in vitro ; for leflunomide and teriflunomide, this was also shown in vivo (Van Gompel et al . 2005, Cook et al . 2010).…”

Section: Discussionmentioning

confidence: 99%

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Combined blockade of signalling pathways shows marked anti-tumour potential in phaeochromocytoma cell lines

Nölting

García

Alusi

et al. 2012

Journal of Molecular Endocrinology

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Currently, there is no completely effective therapy available for metastatic phaeochromocytomas (PCCs) and paragangliomas. In this study, we explore new molecular targeted therapies for these tumours, using one more benign (mouse phaeochromocytoma cell (MPC)) and one more malignant (mouse tumour tissue (MTT)) mouse PCC cell line –both generated from heterozygous neurofibromin 1 knockout mice. Several PCC-promoting gene mutations have been associated with aberrant activation of PI3K/AKT, mTORC1 and RAS/RAF/ERK signalling. We therefore investigated different agents that interfere specifically with these pathways, including antagonism of the IGF1 receptor by NVP-AEW541. We found that NVP-AEW541 significantly reduced MPC and MTT cell viability at relatively high doses but led to a compensatory up-regulation of ERK and mTORC1 signalling at suboptimal doses while PI3K/AKT inhibition remained stable. We subsequently investigated the effect of the dual PI3K/mTORC1/2 inhibitor NVP-BEZ235, which led to a significant decrease of MPC and MTT cell viability at doses down to 50 nM but again increased ERK signalling. Accordingly, we next examined the combination of NVP-BEZ235 with the established agent lovastatin, as this has been described to inhibit ERK signalling. Lovastatin alone significantly reduced MPC and MTT cell viability at therapeutically relevant doses and inhibited both ERK and AKT signalling, but increased mTORC1/p70S6K signalling. Combination treatment with NVP-BEZ235 and lovastatin showed a significant additive effect in MPC and MTT cells and resulted in inhibition of both AKT and mTORC1/p70S6K signalling without ERK up-regulation. Simultaneous inhibition of PI3K/AKT, mTORC1/2 and ERK signalling suggests a novel therapeutic approach for malignant PCCs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Combined blockade of signalling pathways shows marked anti-tumour potential in phaeochromocytoma cell lines

Nölting

García

Alusi

et al. 2012

Journal of Molecular Endocrinology

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“…7 However, the biological function of ASCL1 in laryngeal cancer is not known yet. In order to explore the function of ASCL1 in laryngeal cancer, loss-of-function studies were carried out and found that decreased ASCL1 expression could reduce the growth, migration, and invasion of laryngeal cancer cell lines and induce their apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…4 It plays an important role in a series of cellular processes such as intracellular transportation and cell division. 5 Some studies indicated that the abnormal expression and function of ASCL1 protein are crucial to the occurrence of human cancers [6][7][8][9][10][11][12] of many kinds, in which increased ASCL1 expression levels have been detected, and silencing ASCL1 expression could suppress the proliferation of both cancer 6,7,10 and neuroendocrine tumor. 5,13,14 And some report that suppression of ASCL1 expression by RNA interference could lead to cellcycle procession as well as cell differentiation and apoptosis and inhibit growth in vitro in an ASCL1 expression-dependent manner.…”

Section: Introductionmentioning

confidence: 99%

Achaete-scute complex homologue-1 promotes development of laryngocarcinoma via facilitating the epithelial–mesenchymal transformation

Zhang

et al. 2017

Tumour Biol.

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Laryngeal cancer is one of the most common fatal cancers among head and neck carcinomas, whose mechanism, however, remains unclear. The proneural basic-helix-loop-helix protein achaete-scute complex homologue-1, a member of the basic helix-loop-helix family, plays a very important role in many cancers. This study aims to explore the clinical value and mechanism of achaete-scute complex homologue-1 in laryngeal cancer. Methods including Cell Counting Kit-8, flow cytometry, Transwell invasion assays, and scratch assay were adopted to further explore the bio-function of achaetescute complex homologue-1, whose expression was examined in fresh and paraffin chip of laryngeal carcinoma tissues by means of western blot and immunohistochemistry, after the interference of achaete-scute complex homologue-1; achaetescute complex homologue-1, an overexpression in laryngeal carcinoma whose carcinogenicity potential was confirmed via western blot, was correlative with T classification (p = 0.002), histological differentiation (p = 0.000), lymph node metastasis (p = 0.000), and poor survival (p = 0.000). Multivariate analysis shows that achaete-scute complex homologue-1 overexpression is an independent prognostic factor unfavorable to laryngeal carcinoma patients (p = 0.000). Moreover, knocking down achaete-scute complex homologue-1 expression could significantly suppress the proliferation, migration, and invasion of laryngeal carcinoma cell in vitro and disorder epithelial-mesenchymal transformation-associated protein expression. Achaete-scute complex homologue-1 plays an important role in the genesis and progression of laryngeal carcinoma and may act as a potential biomarker for therapeutic target and prognostic prediction.

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“…Although activation of the Ras/Raf/MEK/ERK pathway promotes tumorigenesis in several cancers, it is minimally active or absent in GEP-NETs [39]. Raf-1 activators such as tautomycin and its related compound streptozotocin as well as the anti-rheumatic drug leflunomide have been shown to decrease the expression of NET markers and inhibit in vitro and in vivo carcinoid cell proliferation [40]. Following the demonstration that the Notch 1 signaling pathway acts as a tumor suppressor gene in carcinoid tumors the flavonoid herceptin, a potential Notch 1 activator, has been used as a therapeutic mean.…”

Section: Molecular Classificationmentioning

confidence: 99%

Gastroenteropancreatic neuroendocrine tumors: new insights in the diagnosis and therapy

Alexandraki

Kaltsas

2011

Endocrine

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Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are relatively rare and heterogenous malignancies. Recent advances in histopathological classification according to the anatomical site of origin, proliferation rate, and extend of the disease have created a valid and powerful tool for the prognostic stratification of GEP-NETs. Chromogranin A is still the best available marker used for the biochemical confirmation of these tumors, but new more sensitive markers are urgently required. Although scintigraphy with (111)In-octreotide has widely been applied for the localization and staging of GEP-NETs, newer imaging modalities based on the functional characteristics of these tumors are evolving aiming not only to facilitate the diagnosis but also prognosis and evaluation of treatment. Somatostatin receptors are the primary therapeutic targets through somatostatin analogs and peptide receptor radionuclide therapy (PRRT) producing symptomatic, biochemical and to a lesser extent antiproliferative effects. Due to the relatively limited and erratic response to chemotherapy, new molecular targeted therapies exploiting some of the biological properties of GEP-NETs such as increased vascularity and inhibition of pathways involved in downstream signal transduction have evolved. Some of these therapies, the mTOR inhibitor everolimus and the tyrosine kinase inhibitor sunitinib, have been recently validated in phase III studies producing practice changing outcomes. In addition, two oral chemotherapeutic agents temozolomide and capecitabine, show promising effects and may replace streptozotocin-based regimens whereas combination therapies with the angiogenesis inhibitor bevacizumab are being investigated. Although progression free survival is used as a feasible primary end point due to the long survival of patients even in the presence of extensive disease prolongation of overall survival following the introduction of new therapies needs to be established.

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Identification of a Novel Raf-1 Pathway Activator that Inhibits Gastrointestinal Carcinoid Cell Growth

Cited by 31 publications

References 40 publications

Combined blockade of signalling pathways shows marked anti-tumour potential in phaeochromocytoma cell lines

Combined blockade of signalling pathways shows marked anti-tumour potential in phaeochromocytoma cell lines

Achaete-scute complex homologue-1 promotes development of laryngocarcinoma via facilitating the epithelial–mesenchymal transformation

Gastroenteropancreatic neuroendocrine tumors: new insights in the diagnosis and therapy

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