PEA15 impairs cell migration and correlates with clinical features predicting good prognosis in neuroblastoma.
ERK and RSK2 drive proliferation and invasion of many cancers. Phosphoprotein enriched in astrocytes 15 (PEA15) binds ERK and RSK2 and high PEA15 levels can impair ERK- and RSK2-dependent transcription. PEA15 expression also inversely correlates with cell motility and invasiveness. We therefore tested PEA15 effects on neuroblastoma cells in vitro. We further analyzed PEA15 expression in the context of clinical and genetic features of neuroblastoma in tumor samples to determine its correlation with disease progression. Affymetrix microarray analysis was performed using 24 different neuroblastoma cell lines. Cell lines expressing low to intermediate levels of PEA15 were chosen for in vitro functional studies. The cell line results were verified by Affymetrix analysis of three different neuroblastic tumor types (total of 110 samples) PEA15 overexpression inhibited neuroblastoma migration in vitro. We verified that inhibition of motility required PEA15 interaction with its binding partners ERK and RSK2. Additionally, synthetic inhibitors of RSK2 suppressed integrin-dependent migration. PEA15 expression correlates with clinical parameters and a 25% increase in patient survival rate. The highest PEA15 levels were found in low stage, more differentiated and less metastatic neuroblastic tumors, and correlated with lack of MYCN amplification. PEA15 blocks neuroblastoma migration through inhibition of ERK/RSK2 signaling. PEA15 expression levels correlate with favorable clinical features suggesting that PEA15 limits metastatic progression of neuroblastoma. Thus, PEA15 and its partners ERK and RSK2 are potential targets for the development of new therapeutics to impede progression of minimal residual disease in patients with high-risk neuroblastoma.
Cancer Biology Program, University of Hawai'i Cancer Center, University of Hawai'i at Manoa, Honolulu, HI 96813, USA.
Joanna E
JE
Gawecka
Dirk
D
Geerts
Jan
J
Koster
Maisel J
MJ
Caliva
Florian J
FJ
Sulzmaier
John
J
Opoku-Ansah
Randal K
RK
Wada
André S
AS
Bachmann
Joe W
JW
Ramos
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D019556:COS Cells; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D002522:Chlorocebus aethiops; D002869:Chromosome Aberrations; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005784:Gene Amplification; D006801:Humans; D016023:Integrins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D009687:Nuclear Proteins / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D016023:Integrins; D047908:Intracellular Signaling Peptides and Proteins; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; C092039:PEA15 protein, human; D010750:Phosphoproteins; D012333:RNA, Messenger; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3; D048049:Extracellular Signal-Regulated MAP Kinases