Antiproliferative effects of Bortezomib in endothelial cells transformed by viral G protein-coupled receptor associated to Kaposi's sarcoma

作者：Suares A; Mori Sequeiros Garcia M; Paz C; Gonzalez Pardo V^*

来源：Cellular Signalling, 2017, 32: 124-132.

DOI：10.1016/j.cellsig.2017.01.025

• Bortezomib
• MKP-3
• ERIC1/2
• FOXO1
• vGPCR

The Kaposi's Sarcoma-associated Herpes virus G Protein-Coupled Receptor (vGPCR) is a key molecule in the pathogenesis of Kaposi Sarcoma. We have previously demonstrated that the proteasome inhibitor Bortezomib inhibits NF-KB pathway, which is required for tumor maintenance in endothelial cells that express vGPCR (vGPCR cells). In this work, we further investigated Bortezomib anti-proliferative mechanism of action. We demonstrated that Bortezomib decreases vGPCR cell number in a dose-dependent manner and induces cell morphology changes. Bortezomib decreases ERK1/2 phosphorylation whereas induces the accumulation of MKP-3-a specific ERK1/2 MAP kinase phosphatase in time and concentration dependent manner (1.5-32 h; 0.25-1 nM). The transcription factor FOX01 is activated by dephosphorylation and regulates p21 expression. Here, we demonstrated that Bortezomib increases FOX01 protein and decreases its phosphorylation in a concentration dependent manner (0.25-1 nM). Bortezomib (0.5 nM, 24 h) also increase nuclear FOX01 protein, in line with FOX01 dephosphorylation induced by the drug. Consistent with FOX01 dephosphorylation/activation, p21 mRNA expression is increased by Bortezomib in a MKP-3-dependent way. Bortezomib (0.5 nM, 24 h) also decreases VEGF, an ERK1/2-dependent effect. It is concluded that in vGPCR cells, Bortezomib decreases ERK1/2 and FOX01 phosphorylation through MKP-3 accumulation, leading ERK1/2 deactivation and FOX01 activation respectively and, consequently, to cell proliferation inhibition, p21 induction and VEGF repression. Taken together, all these events contribute to the anti-tumoral effect of Bortezomib.

• 出版日期2017-4