Semaphorin3F Down-Regulates the Expression of Integrin alpha(v)beta(3) and Sensitizes Multicellular Tumor Spheroids to Chemotherapy via the Neuropilin-2 Receptor in vitro

Background: Multicellular resistance (MCR), i.e. decreased sensitivity to anticancer drugs compared with common monolayer cell (MC) cultures, depends partly on tumor cell-cell adhesion. Previous studies have shown that anti-adhesive therapies, including integrin alpha(v), beta(1) and alpha(v)beta(3) targeting, induced apoptosis and reversed the sensitivity of MCR. Methods: A model of three-dimensional cell culture was used to establish HT29 multicellular spheroid cells (MCS) and explore the effect of semaphorin3F (Sema3F) on integrin-mediated cell-cell interactions in MCS of a human colorectal adenocarcinoma cell line (HT29) and sensitization of HT29 MCS to 5-fluorouracil and oxaliplatin via a decrease in integrin alpha(v)beta(3). Results: Elevated expression of Sema3F led to the up-regulation neuropilin-2 (Nrp2) receptor expression and the down-regulation of integrin alpha(v)beta(3) expression. Furthermore, short interfering RNA of Nrp2 could reverse MCR. Conclusion: Our study demonstrates that Sema3F can sensitize MCR by decreasing integrin alpha(v)beta(3) expression via the Nrp2 receptor. Copyright (C) 2009 S. Karger AG, Basel