Targeting nuclear factor-κB suppresses the negative effect of toll-like receptor 4 signaling on antimetastasis therapy based on targeting αvβ3.

The targeting of αvβ3 is a promising therapeutic strategy for suppressing tumor metastasis. However, it is unclear whether the therapeutic efficacy could be influenced by metastasis-promoting factor(s) in vivo. Here we report that Toll-like receptor 4 (TLR4) ligand released from damaged tumor cells or bacteria had a negative effect on the therapeutic effect of a recombinant CBD-HepII polypeptide of fibronectin (CH50) that suppresses tumor metastasis by targeting αvβ3. The TLR4 ligand could antagonize the inhibitory effect of CH50 on tumor cell adhesion and invasion by promoting the expression and activity of αvβ3 in tumor cells. The TLR4 ligand also reduced the antimetastasis effect of CH50 by promoting tumor cell survival in circulation. Moreover, TLR4 ligands released by tumor cells in circulation could increase the survival and proliferation capacity of tumor cells after extravasation, resulting in the formation of more metastatic nodules. The effect of TLR4 signaling was mainly mediated by nuclear factor-κB (NF-κB). Inhibiting NF-κB could abrogate the negative effect of TLR4 ligand, and augment the inhibitory effect of CH50 on tumor metastasis. Consistently, the combination of NF-κB inhibitor and CH50 significantly inhibited metastasis of tumor cells in vivo and prolonged the survival of mice. The findings in this study suggest that the combination of NF-κB inhibitor and αvβ3 antagonist would be a novel therapeutic option for the prevention of tumor metastasis.