ANTINEOPLASTIC EFFECTS OF BORTEZOMIB IN CELLULAR SPHEROIDS FROM ENDOTHELIAL CELLS TRANSFORMED BY KAPOSI SARCOMA-ASSOCIATED HERPES VIRUS G PROTEIN COUPLED RECEPTOR

SUARES A.; TAPIA C; PAZ C.; PARDO V.

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

Sociedades de Biociencias

The potent and selective proteasome inhibitor Bortezomib (Velcade, formerly known as PS-341) has shown remarkable antitumor activity and is currently approved for the treatment of multiple myeloma (Richardson PG, et al., N Engl J Med 348: 2609?2617, 2003). The Kaposi?s Sarcoma-associated Herpes virus G Protein-Coupled Receptor (vGPCR) is a key molecule in the pathogenesis of Kaposi Sarcoma. Persistent expression and activity of vGPCR is required for NF-κB pathway activation and tumor maintenance in endothelial cells. We have previously demonstrated that Bortezomib decreases nuclear activity of NF-κB (González Pardo V, et al., Steroids 1025?1032, 2012; González Pardo V, et al., BJP 169: 1635?1645, 2013) and induces apoptosis in endothelial cells expressing vGPCR by increasing Bim and caspase-3 cleavage (Suares A, et al., Steroids 85-91, 2015). We demonstrated that Bortezomib decreases ERK1/2 and FOXO1 phosphorylation through MKP-3 accumulation in vGPCR cells, leading ERK1/2 deactivation and FOXO1 activation. Consequently, cell proliferation is inhibited by VEGF repression and p21 induction. Taken together, all these events contribute to the anti-tumoral effect of Bortezomib (Suares A, et al., Cell Signal 32: 124-132, 2017). Many types of mammalian cells can aggregate and differentiate into 3-D multicellular spheroids (MCS) when cultured in suspension or a non adhesive environment. Compared to conventional mono-layer cultures (2D-cultures), MCS resemble real tissues better in terms of structural and functional properties (Fang Y and Engler MR, 22: 456?472, 2017). MCS formed by transformed cells are widely used as avascular tumor models for metastasis and invasion research and for therapeutic screening.In this work we develop the technique to obtain MCS from vGPCR cells in order to test whether MCS respond to Bortezomib in a similar way as vGPCR cells in 2D-cultures.