Microarray and Suppression Subtractive Hybridization Analyses of Gene Expression in Pheochromocytoma Cells Reveal Pleiotropic Effects of Pituitary Adenylate Cyclase-Activating Polypeptide on Cell Proliferation, Survival, and Adhesion

Grumolato, Luca; Elkahloun, Abdel G.; Ghzili, Hafida; Dionne‐Laporte, Alexandre; Coulouarn, Cédric; Yon, Laurent; Salier, Jean‐Philippe; Eiden, Lee E.; Fournier, Alain; Vaudry, Hubert; Anouar, Youssef

doi:10.1210/en.2002-0106

Cited by 55 publications

(48 citation statements)

References 55 publications

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“…IL-8 has been shown to contribute to human cancer progression through its mitogenic, angiogenic and migratory action (Xie, 2001). In accordance with a recently published study performed using rat pheochromocytoma PC12 cells (Grumolato et al, 2003), we identify LAMR1 as a PACAP-responsive gene. Finally, tissue inhibitor of metalloproteinase 3 (TIMP3) is recognised as an HGF-responsive gene, as previously shown by Castagnino et al (1998).…”

Section: Discussionsupporting

confidence: 87%

Identification of novel growth factor-responsive genes in neuroendocrine gastrointestinal tumour cells

et al. 2005

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Targeting growth-regulatory pathways is a promising approach in cancer treatment. A prerequisite to the development of such therapies is characterisation of tumour growth regulation in the particular tumour cell type of interest. In order to gain insight into molecular mechanisms underlying proliferative responses in neuroendocrine (NE) gastrointestinal (GI) tumours, we investigated gene expression in human carcinoid BON cells after exposure to gastrin, hepatocyte growth factor (HGF), pituitary adenylate cyclaseactivating polypeptide or epidermal growth factor. We particularly focused on gastrin-and HGF-induced gene expression, and identified 95 gastrin-and 101 HGF-responsive genes. The majority of these genes are known mediators of processes central in tumour biology, and a number of them have been associated with poor prognosis and metastasis in cancer patients. Furthermore, we identified 12 genes that were regulated by all four factors, indicating that they may be universally regulated during NE GI tumour cell proliferation. Our findings provide useful hypotheses for further studies aimed to search for new therapeutic targets as well as tumour markers in NE GI tumours.

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Section: Discussionsupporting

confidence: 87%

Identification of novel growth factor-responsive genes in neuroendocrine gastrointestinal tumour cells

et al. 2005

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“…Despite its limitations, this cell line may help to understand the role of trophic factors in tumorigenesis of chromaffin cells (Grumolato et al 2003a). We showed that both AM and SDF1 significantly increased the number of PC12 cells after a 2-day treatment, compared to untreated cells.…”

Section: Discussionmentioning

confidence: 85%

“…In particular, pituitary adenylate cyclase-activating polypeptide (PACAP), neuropeptide Y (NPY), and adrenomedullin (AM) are trophic and secretion-stimulating peptides that have been characterized in normal adrenomedullary as well as pheochromocytoma cells (Ichiki et al 1994, deS Senanayake et al 1995, Turquier et al 2001, Isobe et al 2003, Conconi et al 2006, Zeng et al 2006. The neuropeptide PACAP is endowed with a neurotrophic activity, exerting neuroprotective effects against various stressors and during cell differentiation (Grumolato et al 2003a). Moreover, a role for PACAP in angiogenesis has been suggested since it stimulates vascular endothelial growth factor expression in numerous tumoral cell types (Ribatti et al 2007).…”

Section: Introductionmentioning

confidence: 99%

Expression of trophic amidated peptides and their receptors in benign and malignant pheochromocytomas: high expression of adrenomedullin RDC1 receptor and implication in tumoral cell survival

Thouënnon¹,

Aimar²,

Tanguy³

et al. 2010

Endocrine-Related Cancer

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Pheochromocytomas are catecholamine-producing tumors which are generally benign, but which can also present as or develop into malignancy. Molecular pathways of malignant transformation remain poorly understood. Pheochromocytomas express various trophic peptides which may influence tumoral cell behavior. Here, we investigated the expression of trophic amidated peptides, including pituitary adenylate cyclase-activating polypeptide (PACAP), neuropeptide Y (NPY), and adrenomedullin (AM), and their receptors in benign and malignant pheochromocytomas in order to assess their potential role in chromaffin cell tumorigenesis and malignant transformation. PACAP, NPY, and AM are expressed in the majority of pheochromocytomas studied; NPY exhibiting the highest mRNA levels relative to reference genes. Although median gene expression or peptide levels were systematically lower in malignant compared to benign tumors, no statistically significant difference was found. Among all the receptors of these peptides that were analyzed, only the AM receptor RDC1 displayed a differential expression between benign and malignant pheochromocytomas. This receptor exhibited a fourfold higher expression in malignant than in benign tumors. AM and stromal cell-derived factor 1, which has also been described as a ligand for RDC1, increased the number of human pheochromocytoma cells in primary culture and exerted anti-apoptotic activity on rat pheochromocytoma PC12 cells. In addition, RDC1 gene silencing decreased the number of viable PC12 cells. This study shows the expression of several trophic peptides and their receptors in benign and malignant pheochromocytomas, and suggests that AM and its RDC1 receptor could be involved in chromaffin cell tumorigenesis through pro-survival effects. Therefore, AM and RDC1 may represent valuable targets for the treatment of malignant pheochromocytomas.

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“…Interestingly, S100A6 is considered a diagnostic marker for pancreatic cancer (32) and is found to be both positively (32) and negatively (33) associated with proliferation and invasion. Notably, S100A6 was also up-regulated during a microarray analysis of rat pheochromocytoma cells compared with terminally differentiated rat adrenomedullary chromaffin cells (34). Regarding other upregulated genes, it is noteworthy that collagen 1a1 (COL1A1), insulin-like growth factor binding protein 2 (IGFBP2), IGFBP7, and lysyl oxidase (LOX)-like 2 (LOXL2) have all been implicated in the tumor phenotype.…”

Section: Resultsmentioning

confidence: 99%

Cells Silenced forSDHBExpression Display Characteristic Features of the Tumor Phenotype

Cervera

Apostolova²,

Crespo³

et al. 2008

Cancer Research

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Recently, enzymes of the tricarboxylic acid (TCA) cycle have emerged as novel tumor suppressors. In particular, mutations in the nuclear-encoded subunits of succinate dehydrogenase (SDHB, SDHC, and SDHD) cause paragangliomas and pheochromocytomas. Although the mechanism(s) by which disruption of mitochondrial metabolism leads to neoplasia is largely unknown, increasing evidence points to an activation of pseudohypoxia. In this study, we have shown that silencing of SDHB using DNA-based small interfering RNA resulted in major impairments in cellular proliferation, respiration, and a corresponding shift to glycolysis. The levels of reactive oxygen species, however, were unchanged. As expected, hypoxiainducible factor-1A (HIF-1A) and HIF-2A were up-regulated in chronically silenced cells, suggesting that a pseudohypoxic state was attained. In addition, the c-Jun amino-terminal kinase and p38 kinase stress signaling proteins were hyperphosphorylated in SDHB-silenced cells. Microarray analysis showed that >400 genes were influenced (6-fold or more up-regulation or down-regulation) by silencing of SDHB, confirming the importance of the TCA cycle in cellular metabolism. Examples of dysregulated genes included those involved in proliferation, adhesion, and the hypoxia pathway. Of interest, SDHB-silenced cells had a greater capacity to adhere to extracellular matrix components, including fibronectin and laminin, than control cells, thus suggesting a possible mechanism of tumor initiation. Although transient silencing of the HIF-1A transcription factor in SDHB-silenced cells had little effect on the expression of a subset of upregulated genes, it partially reversed the adhesion phenotype to fibronectin, pointing to a potentially important role for HIF-1 in this process. [Cancer Res 2008;68(11):4058-67]

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Microarray and Suppression Subtractive Hybridization Analyses of Gene Expression in Pheochromocytoma Cells Reveal Pleiotropic Effects of Pituitary Adenylate Cyclase-Activating Polypeptide on Cell Proliferation, Survival, and Adhesion

Cited by 55 publications

References 55 publications

Identification of novel growth factor-responsive genes in neuroendocrine gastrointestinal tumour cells

Identification of novel growth factor-responsive genes in neuroendocrine gastrointestinal tumour cells

Expression of trophic amidated peptides and their receptors in benign and malignant pheochromocytomas: high expression of adrenomedullin RDC1 receptor and implication in tumoral cell survival

Cells Silenced forSDHBExpression Display Characteristic Features of the Tumor Phenotype

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