Proliferative actions of natriuretic peptides on neuroblastoma cells. Involvement of guanylyl cyclase and non-guanylyl cyclase pathways.
To identify neural tumor cell lines that could be used as models to study growth-related natriuretic peptide actions, we determined the effects of these peptides on the proliferation of human and rodent neuroblastoma cell lines. Subnanomolar concentrations of atrial natriuretic peptide (ANP) and type C natriuretic peptide (CNP) stimulated proliferation in all four cell lines. These actions were associated with cGMP elevation and were blocked by a protein kinase G inhibitor. These data imply the involvement of guanylyl cyclase (GC)-coupled natriuretic receptors. However, higher concentrations of ANP and CNP, and low concentrations of des-[Gln(18),Ser(19),Gly(20),Leu(21),Gly(22)]-ANP(4-23)-NH(2) (desANP(4-23)) (analog for NPR-C receptor) exerted antiproliferative actions in three of the cell lines. These effects were insensitive to a protein kinase G inhibitor and to HS-142-1, suggesting that growth-inhibitory actions involved a non-GC receptor. They did not appear to involve cAMP, protein kinase A, protein kinase C, or calcium mobilization but were abolished when constitutive mitogen-activated protein kinase activity was inhibited. Radioligand binding experiments revealed the presence of a uniform class of binding sites in NG108 cells and multiple binding sites in Neuro2a cells. Northern and reverse transcriptase-polymerase chain reaction analyses revealed differential gene expression for NPR-A/B/C in NG108 and Neuro2a cells. The results indicate that natriuretic peptides stimulate neuroblastoma cell proliferation through type NPR-A/B (GC) receptors. Higher concentrations of ANP and CNP exerted a mitogen-activated protein kinase-dependent antiproliferative action mediated by a non-GC receptor that interacts with desANP(4-23) with relatively high affinity.
Lelièvre
V
V
Department of Psychiatry and Mental Retardation Research Center, UCLA, Neuropsychiatric Institute, Los Angeles, California 90024, USA.
Pineau
N
N
Hu
Z
Z
Ioffe
Y
Y
Byun
J Y
JY
Muller
J M
JM
Waschek
J A
JA
D009320:Atrial Natriuretic Factor / Q000737:chemistry / Q000494:pharmacology*; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects*; D006162:Guanylate Cyclase / Q000378:metabolism*; D008969:Molecular Sequence Data; D009447:Neuroblastoma / Q000473:pathology*; D017461:Receptors, Atrial Natriuretic Factor / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D009320:Atrial Natriuretic Factor; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C073616:atrial natriuretic factor receptor C