Targeting the hedgehog signal transduction pathway at the level of GLI inhibits neuroblastoma cell growth in vitro and in vivo.
Summary of "Targeting the hedgehog signal transduction pathway at the level of GLI inhibits neuroblastoma cell growth in vitro and in vivo."
Hedgehog (HH) signaling is an important regulator of embryogenesis that has been associated with the development of several types of cancer. HH signaling is characterized by Smoothened (SMO)-dependent activation of the GLI transcription factors, which regulate the expression of critical developmental genes. Neuroblastoma, an embryonal tumor of the sympathetic nervous system, was recently shown to express high levels of key molecules in this signaling cascade. Using compounds blocking SMO (cyclopamine and SANT1) or GLI1/GLI2 (GANT61) activity revealed that inhibition of HH signaling at the level of GLI was most effective in reducing neuroblastoma growth. GANT61 sensitivity positively correlated to GLI1 and negatively to MYCN expression in the neuroblastoma cell lines tested. GANT61 downregulated GLI1, c-MYC, MYCN and Cyclin D1 expression and induced apoptosis of neuroblastoma cells. The effects produced by GANT61 were mimicked by GLI knockdown but not by SMO knockdown. Furthermore, GANT61 enhanced the effects of chemotherapeutic drugs used in the treatment of neuroblastoma in an additive or synergistic manner and reduced the growth of established neuroblastoma xenografts in nude mice. Taken together this study suggests that inhibition of HH signaling is a highly relevant therapeutic target for high-risk neuroblastoma lacking MYCN amplification and should be considered for clinical testing. © 2012 Wiley Periodicals, Inc.
Affiliation
Childhood Cancer Research Unit, Department of Women's and Children's Health, Astrid Lindgren Children's Hospital, Karolinska Institutet, Stockholm, Sweden. malin.wickstrom@ki.se.
Journal Details
This article was published in the following journal.
Name: International journal of cancer. Journal international du cancer
ISSN: 1097-0215
Pages:
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/22949014
- DOI: http://dx.doi.org/10.1002/ijc.27820
Medical and Biotech [MESH] Definitions
Signal Transduction
The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activa
Hedgehog Proteins
A family of intercellular signaling proteins that play and important role in regulating the development of many TISSUES and organs. Their name derives from the observation of a hedgehog-like appearance in DROSOPHILA embryos with genetic mutations that block their action.
Rhob Gtp-binding Protein
A GTP-BINDING PROTEIN involved in regulating a signal transduction pathway that controls assembly of focal adhesions and actin stress fibers. This enzyme was formerly listed as EC 3.6.1.47.
Olfactory Marker Protein
A ubiquitous, cytoplasmic protein found in mature OLFACTORY RECEPTOR NEURONS of all VERTEBRATES. It is a modulator of the olfactory SIGNAL TRANSDUCTION PATHWAY.
Smad6 Protein
An inhibitory Smad protein that negatively regulates the SIGNAL TRANSDUCTION PATHWAYS from BONE MORPHOGENETIC PROTEIN RECEPTORS. Smad6 inhibits PHOSPHORYLATION of SMAD2 PROTEIN and SMAD3 PROTEIN.
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