PED/PEA-15 MODULATES COXSACKIE AND ADENOVIRUS RECEPTOR (CAR) EXPRESSION AND ADENOVIRAL INFECTIVITY VIA ERK-MEDIATED SIGNALS IN GLIOMA CELLS.

Abstract Aims: Glioblastoma multiforme (GBM) is the most aggressive human brain tumour, and is highly resistant to chemo and radiotherapy. Selective replicating oncolytic viruses represent a novel approach for the treatment of neoplastic diseases. Coxsackie and 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 localisation will contribute to increase the efficacy of oncolytic adenoviruses. Results. Two glioma cell lines (U343MG and U373MG) were infected with the oncolytic adenovirus dl922-947. U373MG cells were more susceptible to cell death following viral infection, compared to 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 decreased ERK1/2 nuclear/cytosolic ratio, compared to U343MG cells. Intracellular content of PED/PEA-15, an ERK1/2 interacting protein, was also augumented 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. Conclusions: 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.