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Effects of the ruthenium-based drug NAMI-A on the roles played by TGF-β1 in the metastatic process

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Abstract

The ruthenium-based drug NAMI-A, characterised by its selectivity against solid tumour metastases, promotes TGF-β1-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-β1 in the process of metastasis formation. NAMI-A (1) affects the secretion of TGF-β1 in metastatic MDA-MB-231 cells rather than in non-tumorigenic HBL-100 cells, (2) prevails over TGF-β1 with regard to the invasive capacity of the treated cells, and (3) contrasts integrin-dependent migration stimulated by TGF-β1. It, thus, appears that the effects of NAMI-A on cell invasion and migration are best summarised as an interference with TGF-β1 and a reduction of its activity in these events. At a molecular level, the similar activity of NAMI-A and TGF-β1 on RhoA GTPase supports its interaction with cell surface integrins while TGF-β1 can activate it by interaction with its TGFβR receptor. The inhibition of TGF-β1-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-β1 in cancer metastasis are insufficient to attribute the responsibility for the anti-metastatic activity of the ruthenium-based drug to this target alone.

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Abbreviations

BSA:

Bovine serum albumin

CHK1:

Checkpoint kinase 1

CMF-DPBS:

Calcium and Magnesium Free Dulbecco’s Phosphate Buffered Saline

ECM:

Extracellular matrix

DMEM:

Dulbecco’s modified Eagle’s medium

DPBS:

Dulbecco’s Phosphate Buffered Saline

FBS:

Foetal bovine serum

GRP78:

78 kDa glucose-regulated protein

LB:

Lysis buffer

MMPs:

Matrix metallo proteinases

NAMI-A:

Imidazolium trans-imidazoletetrachlororuthenate

ROS:

Reactive oxygen species

SRB:

Sulforhodamine B

TCA:

Trichloro acetic acid

TGF-β1:

Transforming growth factor beta 1

TIMPs:

Tissue inhibitors of MMPs

TMB:

3,3′,5,5′-Tetramethylbenzidine

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Authors and Affiliations

  1. Callerio Foundation Onlus, via A. Fleming 22, 34127, Trieste, Italy

    L. Brescacin, A. Masi, G. Sava & A. Bergamo

  2. Department of Life Sciences, University of Trieste, via A. Fleming 22, 34127, Trieste, Italy

    G. Sava

Authors
  1. L. Brescacin
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  2. A. Masi
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  3. G. Sava
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  4. A. Bergamo
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Corresponding author

Correspondence to A. Bergamo.

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Brescacin, L., Masi, A., Sava, G. et al. Effects of the ruthenium-based drug NAMI-A on the roles played by TGF-β1 in the metastatic process. J Biol Inorg Chem 20, 1163–1173 (2015). https://doi.org/10.1007/s00775-015-1297-8

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