PED/PEA-15 modulates coxsackievirus-adenovirus receptor expression and adenoviral infectivity via ERK-mediated signals in glioma cells.
Glioblastoma multiforme (GBM) is the most aggressive human brain tumor, and is highly resistant to chemo- and radiotherapy. Selectively replicating oncolytic viruses represent a novel approach for the treatment of neoplastic diseases. Coxsackievirus-adenovirus receptor (CAR) is the primary receptor for adenoviruses, and loss or reduction of CAR greatly decreases adenoviral entry. Understanding the mechanisms regulating CAR expression and localization will contribute to increase the efficacy of oncolytic adenoviruses. Two glioma cell lines (U343MG and U373MG) were infected with the oncolytic adenovirus dl922-947. U373MG cells were more susceptible to cell death after viral infection, compared with U343MG cells. The enhanced sensitivity was paralleled by increased adenoviral entry and CAR mRNA and protein levels in U373MG cells. In addition, U373MG cells displayed a decreased ERK1/2 (extracellular signal-regulated kinase-1/2) nuclear-to-cytosolic ratio, compared with U343MG cells. Intracellular content of PED/PEA-15, an ERK1/2-interacting protein, was also augmented in these cells. Both ERK2 overexpression and genetic silencing of PED/PEA-15 by antisense oligonucleotides increased ERK nuclear accumulation and reduced CAR expression and adenoviral entry. Our data indicate that dl922-947 could represent an useful tool for the treatment of GBM and that PED/PEA-15 modulates CAR expression and adenoviral entry, by sequestering ERK1/2.
Botta
Ginevra
G
Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università Federico II, Naples, Italy.
Perruolo
Giuseppe
G
Libertini
Silvana
S
Cassese
Angela
A
Abagnale
Antonella
A
Beguinot
Francesco
F
Formisano
Pietro
P
Portella
Giuseppe
G
D000256:Adenoviridae / Q000502:physiology*; D000257:Adenoviridae Infections / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins; D016923:Cell Death; D045744:Cell Line, Tumor; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005910:Glioma / Q000201:enzymology* / Q000473:pathology / Q000821:virology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D010750:Phosphoproteins / Q000378:metabolism*; D021381:Protein Transport; D011991:Receptors, Virus / Q000378:metabolism*; D014162:Transfection
D051017:Apoptosis Regulatory Proteins; C568771:CLMP protein, human; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D047908:Intracellular Signaling Peptides and Proteins; C092039:PEA15 protein, human; D010750:Phosphoproteins; D011991:Receptors, Virus; D048049:Extracellular Signal-Regulated MAP Kinases