Inhibition of invasion and induction of apoptotic cell death of cancer cell lines by overexpression of TIMP-3

Abstract

Dysregulation of matrix degrading metalloproteinase enzymes (MMPs) leads to increased extracellular matrix turnover, a key event in the local invasion and metastasis of many tumours. The tissue inhibitors of metalloproteinases (TIMPs) limit the activity of MMPs, which suggests their use in gene therapy. We have previously shown that overexpression of TIMP-1, -2 or -3 inhibits vascular smooth muscle and melanoma cell invasion, while TIMP-3 uniquely promotes apoptosis. We have therefore sought to determine whether TIMP-3 can inhibit invasion and promote apoptosis in other cancer cell types. Adenoviral-mediated overexpression of TIMP-3 inhibited invasion of HeLa and HT1080 cells through artificial basement membrane to similar levels as that achieved by TIMP-1 and -2. However, TIMP-3 uniquely promoted cell cycle entry and subsequent death by apoptosis. Apoptosis was confirmed by morphological analysis, terminal dUTP nick end labelling (TUNEL) and flow cytometry. The apoptotic phenotype was mimicked by addition of exogenous recombinant TIMP-3 to uninfected cultures demonstrating that the death signal is initiated extracellularly and that a bystander effect exists. These results show that TIMP-3 inhibits invasion in vitro and promotes apoptosis in cancer cell type of differing origin. This clearly identifies the potential of TIMP-3 for gene therapy of multiple cancer types.

References 34

1. 1.

   Ahonen M., Baker A. H., Kähäri V. M. Adenovirus-mediated gene delivery of tissue inhibitor of metalloproteinases-3 inhibits invasion and induces apoptosis in melanoma cells. Cancer Res. 1998;58(11):2310-2315.

   Not in our library

2. 2.

   Apte S. S., Hayashi K., Seldin M. F., Mattei M. G., Hayashi M., Olsen B. R. Gene encoding a novel murine tissue inhibitor of metalloproteinases (TIMP), TIMP-3, is expressed in developing mouse epithelia, cartilage, and muscle, and is located on mouse chromosome 10. Dev Dyn. 1994;200(3):177-197.

   Not in our library10.1002/aja.1002000302

3. 3.

   Baker A. H., Wilkinson G. W., Hembry R. M., Murphy G., Newby A. C. Development of recombinant adenoviruses that drive high level expression of the human metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 and -2 genes: characterization of their infection into rabbit smooth muscle cells and human MCF-7 adenocarcinoma cells. Matrix Biol. 1996;15(6):383-395.

   Not in our library10.1016/s0945-053x(96)90158-4

4. 4.

   Baker A. H., Zaltsman A. B., George S. J., Newby A. C. Divergent effects of tissue inhibitor of metalloproteinase-1, -2, or -3 overexpression on rat vascular smooth muscle cell invasion, proliferation, and death in vitro. TIMP-3 promotes apoptosis. J Clin Invest. 1998;101(6):1478-1487.

   Not in our library10.1172/jci1584

5. 5.

   Bass K. E., Li H., Hawkes S. P., Howard E., Bullen E., Vu T. K., McMaster M., Janatpour M., Fisher S. J. Tissue inhibitor of metalloproteinase-3 expression is upregulated during human cytotrophoblast invasion in vitro. Dev Genet. 1997;21(1):61-67.

   Not in our library10.1002/(sici)1520-6408(1997)21:1<61::aid-dvg7>3.0.co;2-6

6. 6.

   Birkedal-Hansen H., Moore W. G., Bodden M. K., Windsor L. J., Birkedal-Hansen B., DeCarlo A., Engler J. A. Matrix metalloproteinases: a review. Crit Rev Oral Biol Med. 1993;4(2):197-250.

   Not in our library10.1177/10454411930040020401

7. 7.

   Bode W., Reinemer P., Huber R., Kleine T., Schnierer S., Tschesche H. The X-ray crystal structure of the catalytic domain of human neutrophil collagenase inhibited by a substrate analogue reveals the essentials for catalysis and specificity. EMBO J. 1994;13(6):1263-1269.

   Not in our library10.1002/j.1460-2075.1994.tb06378.x

8. 8.

   Byrne J. A., Tomasetto C., Rouyer N., Bellocq J. P., Rio M. C., Basset P. The tissue inhibitor of metalloproteinases-3 gene in breast carcinoma: identification of multiple polyadenylation sites and a stromal pattern of expression. Mol Med. 1995;1(4):418-427.

   Not in our library

9. 9.

   DeClerck Y. A., Perez N., Shimada H., Boone T. C., Langley K. E., Taylor S. M. Inhibition of invasion and metastasis in cells transfected with an inhibitor of metalloproteinases. Cancer Res. 1992;52(3):701-708.

   Not in our library

10. 10.

    Docherty A. J., Lyons A., Smith B. J., Wright E. M., Stephens P. E., Harris T. J., Murphy G., Reynolds J. J. Sequence of human tissue inhibitor of metalloproteinases and its identity to erythroid-potentiating activity. Nature. 1985;318(6041):66-69.

    Not in our library10.1038/318066a0

11. 11.

    Forough R., Koyama N., Hasenstab D., Lea H., Clowes M., Nikkari S. T., Clowes A. W. Overexpression of tissue inhibitor of matrix metalloproteinase-1 inhibits vascular smooth muscle cell functions in vitro and in vivo. Circ Res. 1996;79(4):812-820.

    Not in our library10.1161/01.res.79.4.812

12. 12.

    George S. J., Johnson J. L., Angelini G. D., Newby A. C., Baker A. H. Adenovirus-mediated gene transfer of the human TIMP-1 gene inhibits smooth muscle cell migration and neointimal formation in human saphenous vein. Hum Gene Ther. 1998;9(6):867-877.

    Not in our library10.1089/hum.1998.9.6-867

13. 13.

    Imren S., Kohn D. B., Shimada H., Blavier L., DeClerck Y. A. Overexpression of tissue inhibitor of metalloproteinases-2 retroviral-mediated gene transfer in vivo inhibits tumor growth and invasion. Cancer Res. 1996;56(13):2891-2895.

    Not in our library

14. 14.

    Koop S., Khokha R., Schmidt E. E., MacDonald I. C., Morris V. L., Chambers A. F., Groom A. C. Overexpression of metalloproteinase inhibitor in B16F10 cells does not affect extravasation but reduces tumor growth. Cancer Res. 1994;54(17):4791-4797.

    Not in our library

15. 15.

    Leco K. J., Apte S. S., Taniguchi G. T., Hawkes S. P., Khokha R., Schultz G. A., Edwards D. R. Murine tissue inhibitor of metalloproteinases-4 (Timp-4): cDNA isolation and expression in adult mouse tissues. FEBS Lett. 1997;401(2-3):213-217.

    Not in our library10.1016/s0014-5793(96)01474-3

16. 16.

    Leco K. J., Khokha R., Pavloff N., Hawkes S. P., Edwards D. R. Tissue inhibitor of metalloproteinases-3 (TIMP-3) is an extracellular matrix-associated protein with a distinctive pattern of expression in mouse cells and tissues. J Biol Chem. 1994;269(12):9352-9360.

    Not in our library

17. 17.

    Low J. A., Johnson M. D., Bone E. A., Dickson R. B. The matrix metalloproteinase inhibitor batimastat (BB-94) retards human breast cancer solid tumor growth but not ascites formation in nude mice. Clin Cancer Res. 1996;2(7):1207-1214.

    Not in our library

18. 18.

    Montgomery A. M., Mueller B. M., Reisfeld R. A., Taylor S. M., DeClerck Y. A. Effect of tissue inhibitor of the matrix metalloproteinases-2 expression on the growth and spontaneous metastasis of a human melanoma cell line. Cancer Res. 1994;54(20):5467-5473.

    Not in our library

19. 19.

    Murphy G., Willenbrock F., Ward R. V., Cockett M. I., Eaton D., Docherty A. J. The C-terminal domain of 72 kDa gelatinase A is not required for catalysis, but is essential for membrane activation and modulates interactions with tissue inhibitors of metalloproteinases. Biochem J. 1992;283(Pt 3):637-641.

    Not in our library10.1042/bj2830637

20. 20.

    Noël A. C., Callé A., Emonard H. P., Nusgens B. V., Simar L., Foidart J., Lapiere C. M., Foidart J. M. Invasion of reconstituted basement membrane matrix is not correlated to the malignant metastatic cell phenotype. Cancer Res. 1991;51(1):405-414.

    Not in our library

21. 21.

    Nuovo G. J. In situ detection of PCR-amplified metalloproteinase cDNAs, their inhibitors and human papillomavirus transcripts in cervical carcinoma cell lines. Int J Cancer. 1997;71(6):1056-1060.

    Not in our library10.1002/(sici)1097-0215(19970611)71:6<1056::aid-ijc23>3.0.co;2-a

22. 22.

    Sledge G. W., Qulali M., Goulet R., Bone E. A., Fife R. Effect of matrix metalloproteinase inhibitor batimastat on breast cancer regrowth and metastasis in athymic mice. J Natl Cancer Inst. 1995;87(20):1546-1550.

    Not in our library10.1093/jnci/87.20.1546

23. 23.

    Smith M. R., Kung H., Durum S. K., Colburn N. H., Sun Y. TIMP-3 induces cell death by stabilizing TNF-alpha receptors on the surface of human colon carcinoma cells. Cytokine. 1997;9(10):770-780.

    Not in our library10.1006/cyto.1997.0233

24. 24.

    Stetler-Stevenson W. G., Brown P. D., Onisto M., Levy A. T., Liotta L. A. Tissue inhibitor of metalloproteinases-2 (TIMP-2) mRNA expression in tumor cell lines and human tumor tissues. J Biol Chem. 1990;265(23):13933-13938.

    Not in our library

25. 25.

    Strongin A. Y., Collier I., Bannikov G., Marmer B. L., Grant G. A., Goldberg G. I. Mechanism of cell surface activation of 72-kDa type IV collagenase. Isolation of the activated form of the membrane metalloprotease. J Biol Chem. 1995;270(10):5331-5338.

    Not in our library10.1074/jbc.270.10.5331

26. 26.

    Sun Y., Kim H., Parker M., Stetler-Stevenson W. G., Colburn N. H. Lack of suppression of tumor cell phenotype by overexpression of TIMP-3 in mouse JB6 tumor cells identification of a transfectant with increased tumorigenicity and invasiveness. Anticancer Res. 1996;16(1):1-7.

    Not in our library

27. 27.

    Uría J. A., Ferrando A. A., Velasco G., Freije J. M., López-Otín C. Structure and expression in breast tumors of human TIMP-3, a new member of the metalloproteinase inhibitor family. Cancer Res. 1994;54(8):2091-2094.

    Not in our library

28. 28.

    Wang M., Liu Y. E., Greene J., Sheng S., Fuchs A., Rosen E. M., Shi Y. E. Inhibition of tumor growth and metastasis of human breast cancer cells transfected with tissue inhibitor of metalloproteinase 4. Oncogene. 1997;14(23):2767-2774.

    Not in our library10.1038/sj.onc.1201245

29. 29.

    Wang X., Fu X., Brown P. D., Crimmin M. J., Hoffman R. M. Matrix metalloproteinase inhibitor BB-94 (batimastat) inhibits human colon tumor growth and spread in a patient-like orthotopic model in nude mice. Cancer Res. 1994;54(17):4726-4728.

    Not in our library

30. 30.

    Watanabe M., Takahashi Y., Ohta T., Mai M., Sasaki T., Seiki M. Inhibition of metastasis in human gastric cancer cells transfected with tissue inhibitor of metalloproteinase 1 gene in nude mice. Cancer. 1996;77(8 Suppl):1676-1680.

    Not in our library10.1002/(sici)1097-0142(19960415)77:8<1676::aid-cncr38>3.0.co;2-v

31. 31.

    Watson S. A., Morris T. M., Parsons S. L., Steele R. J., Brown P. D. Therapeutic effect of the matrix metalloproteinase inhibitor, batimastat, in a human colorectal cancer ascites model. Br J Cancer. 1996;74(9):1354-1358.

    Not in our library10.1038/bjc.1996.549

32. 32.

    Wick M., Bürger C., Brüsselbach S., Lucibello F. C., Müller R. A novel member of human tissue inhibitor of metalloproteinases (TIMP) gene family is regulated during G1 progression, mitogenic stimulation, differentiation, and senescence. J Biol Chem. 1994;269(29):18953-18960.

    Not in our library

33. 33.

    Wilkinson G. W., Akrigg A. Constitutive and enhanced expression from the CMV major IE promoter in a defective adenovirus vector. Nucleic Acids Res. 1992;20(9):2233-2239.

    Not in our library10.1093/nar/20.9.2233

34. 34.

    Yang T. T., Hawkes S. P. Role of the 21-kDa protein TIMP-3 in oncogenic transformation of cultured chicken embryo fibroblasts. Proc Natl Acad Sci U S A. 1992;89(22):10676-10680.

    Not in our library10.1073/pnas.89.22.10676

Cited by papers we hold 2

• The Roles of Matrix Metalloproteinases and Their Inhibitors in Human Diseases · 2020
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• MicroRNA-21 regulates breast cancer invasion partly by targeting tissue inhibitor of metalloproteinase 3 expression · 2010
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