Effects of the ruthenium-based drug NAMI-A on the roles played by TGF-ß1 in the metastatic process.

ABSTRACT

The ruthenium-based drug NAMI-A, characterised by its selectivity against solid tumour metastases, promotes TGF-ß1-dependent fibrosis and the reduction of the release of MMPs in the primary tumour. The aim of the study was to examine the interaction of NAMI-A with TGF-ß1 in the process of metastasis formation. NAMI-A (1) affects the secretion of TGF-ß1 in metastatic MDA-MB-231 cells rather than in non-tumorigenic HBL-100 cells, (2) prevails over TGF-ß1 with regard to the invasive capacity of the treated cells, and (3) contrasts integrin-dependent migration stimulated by TGF-ß1. It, thus, appears that the effects of NAMI-A on cell invasion and migration are best summarised as an interference with TGF-ß1 and a reduction of its activity in these events. At a molecular level, the similar activity of NAMI-A and TGF-ß1 on RhoA GTPase supports its interaction with cell surface integrins while TGF-ß1 can activate it by interaction with its TGFßR receptor. The inhibition of TGF-ß1-induced migration of MDA-MB-231 cells by NAMI-A cannot simply be attributed to a modulation of the Smad2 and p38MAPK pathways. In conclusion, the effects of NAMI-A on the biological role of TGF-ß1 in cancer metastasis are insufficient to attribute the responsibility for the anti-metastatic activity of the ruthenium-based drug to this target alone.