An autocrine loop involving ret and glial cell-derived neurotrophic factor mediates retinoic acid-induced neuroblastoma cell differentiation.
In several neuroblastoma cell lines, retinoic acid (RA)-induced differentiation is coupled to increased expression of functional neurotrophic factor receptors, including Trk family receptors and the glial cell-derived neurotrophic factor receptor, Ret. In several cases, increased expression is dependent on signaling through TrkB. Unlike TrkA and TrkB, Ret has never been implicated as a prognostic marker for neuroblastomas. SK-N-BE(2) cells do not express any of Trk family receptors; therefore, they are a choice system to study the specific role of Ret in RA-induced differentiation. Using a 2'-fluoro-RNA aptamer and a truncated Ret protein as specific inhibitors of Ret, we show that RA-induced differentiation is mediated by a positive autocrine loop that sustains Ret downstream signaling and depends on glial cell-derived neurotrophic factor expression and release. This report shows that in SK-N-BE(2) cells, stimulation of Ret is a major upstream mechanism needed to mediate RA-induced differentiation. These results provide important insights on the molecular mechanism of RA action, which might be relevant for the development of biologically based therapeutic strategies.
Cerchia
Laura
L
Istituto per l'Endocrinologia e l'Oncologia Sperimentale del Consiglio Nazionale delle Ricerche G. Salvatore, Naples, Italy.
D'Alessio
Amelia
A
Amabile
Giovanni
G
Duconge
Frederic
F
Pestourie
Carine
C
Tavitian
Bertrand
B
Libri
Domenico
D
de Franciscis
Vittorio
V
D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D019281:Dimerization; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*
D051100:Glial Cell Line-Derived Neurotrophic Factor; D014212:Tretinoin; D051096:Proto-Oncogene Proteins c-ret; D048049:Extracellular Signal-Regulated MAP Kinases