KIT receptor activation by autocrine and paracrine stem cell factor stimulates growth of merkel cell carcinoma in vitro

Autor: Nektarios Tavernarakis, Jürgen Eberle, Maria Metaxari, Efstathios N. Stathopoulos, Konstantin Krasagakis, George N. Tzanakakis, Sabine Krüger-Krasagakis, Irene Fragiadaki, Androniki D. Tosca
Rok vydání: 2011
Předmět:
MAPK/ERK pathway
Physiology
Clinical Biochemistry
Stem cell factor
Biology
Piperazines
Wortmannin
Phosphatidylinositol 3-Kinases
03 medical and health sciences
chemistry.chemical_compound
Paracrine signalling
0302 clinical medicine
Cell Line
Tumor
Paracrine Communication
medicine
Humans
RNA
Messenger
Phosphorylation
Extracellular Signal-Regulated MAP Kinases
Autocrine signalling
Protein kinase B
Cell Proliferation
030304 developmental biology
Stem Cell Factor
0303 health sciences
Reverse Transcriptase Polymerase Chain Reaction
Merkel cell carcinoma
Cell Biology
medicine.disease
Antibodies
Neutralizing
3. Good health
Carcinoma
Merkel Cell
Gene Expression Regulation
Neoplastic
Autocrine Communication
Proto-Oncogene Proteins c-kit
Pyrimidines
Solubility
chemistry
030220 oncology & carcinogenesis
Benzamides
Imatinib Mesylate
Cancer research
Signal transduction
Proto-Oncogene Proteins c-akt
Signal Transduction
Zdroj: Journal of Cellular Physiology
ISSN: 0021-9541
Popis: The co-expression of KIT receptor and its ligand stem cell factor (SCF) has been reported in biopsy specimens of Merkel cell carcinoma (MCC). However, the functional role of SCF/KIT in the pathogenesis of this aggressive tumor has not been elucidated. The present study reports expression and effects of SCF and KIT in the Merkel cell carcinoma cell line MCC-1 in vitro. SCF and KIT were endogenously co-expressed in MCC-1 cells. Exogenous soluble SCF modulated KIT receptor mRNA and protein expression, stimulated growth of MCC-1 cells, upregulated endogenous activation of KIT, AKT, and of extracellular signal-regulated kinase (ERK) 1/2 signaling pathway. On the contrary, an inhibitory antibody that neutralized the KIT ligand binding site, reduced growth of MCC-1 cells, as did high doses of the KIT kinase inhibitors imatinib and nilotinib. Also, inhibitors of KIT downstream effectors, U0126 that blocks MEK1/2 as well as wortmannin and LY294002 that inhibit phosphatidylinositol 3-kinase-dependent AKT phosphorylation, inhibited the proliferation of MCC-1 cells. These data support the hypothesis that KIT is activatable by paracrine or autocrine tumor cell-derived SCF and stimulates growth of Merkel cell carcinoma in vitro. Blockade of KIT and the downstream signaling cascade at various levels results in inhibition of Merkel cell carcinoma growth in vitro, suggesting targets for therapy of this cancer. J. Cell. Physiol. 226: 1099–1109, 2011. © 2010 Wiley-Liss, Inc.
Databáze: OpenAIRE
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