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Full-length ADAMTS-1 and the ADAMTS-1 fragments display pro- and antimetastatic activity, respectively

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Abstract

The exact role of a disintegrin and metalloproteinase with thrombospondin motifs-1 (ADAMTS-1) and the underlying mechanism of its involvement in tumor metastasis have not been established. We have now demonstrated that overexpression of ADAMTS-1 promotes pulmonary metastasis of TA3 mammary carcinoma and Lewis lung carcinoma cells and that a proteinase-dead mutant of ADAMTS-1 (ADAMTS-1E/Q) inhibits their metastasis, indicating that the prometastatic activity of ADAMTS-1 requires its metalloproteinase activity. Overexpression of ADAMTS-1 in these cells promoted tumor angiogenesis and invasion, shedding of the transmembrane precursors of heparin-binding epidermal growth factor (EGF) and amphiregulin (AR), and activation of the EGF receptor and ErbB-2, while overexpression of ADAMTS-1E/Q inhibited these events. Furthermore, we found that ADAMTS-1 undergoes auto-proteolytic cleavage to generate the NH2- and COOH-terminal cleavage fragments containing at least one thrombospondin-type-I-like motif and that overexpression of the NH2-terminal ADAMTS-1 fragment and the COOH-terminal ADAMTS-1 fragment can inhibit pulmonary tumor metastasis. These fragments also inhibited Erk1/2 kinase activation induced by soluble heparin-binding EGF and AR. Taken together, our results suggest that the proteolytic status of ADAMTS-1 determines its effect on tumor metastasis, and that the ADAMTS-1E/Q and the ADAMTS-1 fragments likely inhibit tumor metastasis by negatively regulating the availability and activity of soluble heparin-binding EGF and AR.

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Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

ADAMTS-1:

a disintegrin and metalloproteinase with thrombospondin motifs-1

ADAMTS-1E/Q:

a protease-dead ADAMTS-1 mutant

ADAMTS-1NTF:

the NH2-terminal ADAMTS-1 fragment

ADAMTS-1CTF:

the COOH-terminal ADAMTS-1 fragment

ADAMTSNTCF:

the NH2-terminal cleavage fragment of ADAMTS-1

ADAMTSCTCF:

the COOH-terminal cleavage of ADAMTS-1

APMA:

p-aminophenylmercuric acetate

AR:

amphiregulin

bFGF:

basic fibroblast growth factor

BrdU:

5-bromo-2′-deoxy-uridine

CMFDA:

Green 5-chloromethyl-fluorescein diacetate

Cys-rich:

cysteine-rich

DMEM:

Dulbecco's modified Eagle's medium

ECM:

extracellular matrix

EGF:

epidermal growth factor

EGFR:

epidermal growth factor receptor

FBS:

fetal bovine serum

GAG:

glycosaminoglycans

GF:

growth factors

HS:

heparan sulfate

HSPGs:

heparan sulfate proteoglycans

HB-EGF:

heparin-binding epidermal growth factor

H&E:

hematoxylin and eosin

HUVECs:

human umbilical vein endothelial cells

kDa:

kilodalton

LLC:

Lewis lung carcinoma

MMP:

matrix metalloproteinase

RT–PCR:

reverse transcriptase–polymerase chain reaction

PKC:

protein kinase C

TA3:

TA3 murine mammary carcinoma

TPA:

12-O-tetradecanoyl-phorbol-13-acetate

TSP-1:

thrombospondin type I-like

Tsp-1:

thrombospondin-1

Tsp-2:

thrombospondin-2

VEGF:

vascular endothelial growth factor

vWF:

von Willebrand factor

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Acknowledgements

We thank Dr Deborah McClellan for excellent editorial assistance. This work was supported by a fund from NIH (RO1HL074117).

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  1. Y-j Liu and Y Xu: These authors contributed equally to this work.

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  1. Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Y-j Liu, Y Xu & Q Yu

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Correspondence to Q Yu.

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Liu, Yj., Xu, Y. & Yu, Q. Full-length ADAMTS-1 and the ADAMTS-1 fragments display pro- and antimetastatic activity, respectively. Oncogene 25, 2452–2467 (2006). https://doi.org/10.1038/sj.onc.1209287

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