MKP-3 IS UPREGULATED IN APOPTOSIS INDUCED BY BORTEZOMIB IN ENDOTHELIAL TUMOR CELLS

SUARES A; MORI SEQUEIROS GARCIA MM; PAZ C; GONZALEZ PARDO V

Mar del Plata, Buenos Aires

Congreso; LI Reunión Anual Sociedad Argentina de Investigación en Bioquímica y Biología Molecular; 2015

Sociedad Argentina de Investigación en Bioquímica y Biología Molecular

The Kaposi?s Sarcoma-associated Herpes virus GProtein-Coupled Receptor (vGPCR) is a key molecule in the pathogenesis ofKaposi Sarcoma. Persistent expression and activity of vGPCR is required forNF-kB pathway activation and tumor maintenance in endothelial cells. We havepreviously demonstrated that bortezomib decreases nuclear activity of NF-kB and induces apoptosis inendothelial cells expressing vGPCR. In this work, we investigated whetherbortezomib regulated an ERK specific MAPK phosphatase-3 (MKP-3) expression aspart of its antiproliferative effects in vGPCR cells. The results showed thatbortezomib decreased vGPCR cell number and induced cell morphology changes in adose-dependent manner. In addition, Bortezomib increased MKP-3 protein expressionfollowed by a reduction of FOXO1 and ERK1/2 phosphorylation. These changes wereaccompanied by a reduction of nuclear ERK1/2 phosphorylation and actin cytoskeletonreorganization. In line with FOXO1 dephosphorylation/activation, p21 mRNAlevels were found increased upon bortezomib treatment. Taken together, wepropose that MKP-3 decreases ERK1/2 and FOXO1 phosphorylation, which turns intoFOXO1 activation, and increases p21 mRNA as part of bortezomib actions in vGPCRcells.