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Suppression of matrix metalloproteinase-2 gene expression and invasion in human glioma cells by MMAC/PTEN

Oncogene volume 20, pages 6669–6678 (2001)Cite this article

Abstract

Human gliomas are highly invasive, and remain to be a major obstacle for any effective therapeutic remedy. Among many other factors, gliomas express elevated levels of matrix metalloproteinases (MMPs), which have been implicated to play an important role in tumor invasion as well as neovascularization. The tumor suppressor gene mutated in multiple advanced cancers/phosphatase and tensin homologue (MMAC/PTEN) has been shown to inhibit cell migration, spreading, and focal adhesion. In this study, we determined whether MMAC/PTEN inhibits tumor invasion by modulating MMP-2 activity. Our results showed that reintroduction of the MMAC/PTEN gene into human glioma U251 and U87 cells modified their phenotype and growth characteristics. The ability of MMAC/PTEN to induce anoikis in U251 cells was accompanied by a significant inhibition of in vitro invasion (70%). Expression of MMAC/PTEN in U251 and U87 cells inhibited MMP-2 enzymatic activity as determined by zymography. Furthermore, MMAC/PTEN expression strongly decreased MMP-2 mRNA levels, which correlated well with the inhibition of invasion capacity in these cells. Concomitant with MMP-2 expression and activity, MMP-2 promoter activity was also reduced in MMAC/PTEN expressing cells. Our observations suggest that MMAC/PTEN inhibits tumor cell invasion in part by regulating MMP-2 gene transcription and thereby its enzymatic activity. Further characterization of this regulation will facilitate the development of MMAC/PTEN based gene therapy for gliomas.

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Abbreviations

MMAC/PTEN:

mutated in multiple advanced cancers/phosphatase and tensin homologue

ECM:

extracellular matrix

MMP:

matrix metalloproteinases

TIMPs:

tissue inhibitors of metalloproteinases

CM:

conditioned medium

DMEM:

Dulbecco's modified Eagle's medium.

References

  • Agarwal C, Hembree JR, Rorke EA, Eckert RL . 1994 Cancer Res. 54: 943–949

  • Albelda SM . 1993 Lab. Invest. 68: 4–17

  • Albini A, Melchiori A, Santi L, Liotta LA, Brown PD, Stetler-Stevenson WG . 1991 J. Natl. Cancer Inst. 83: 775–779

  • Apodaca GT, Rutka K, Bouhana ME, Berens JR, Giblin ML, Rosenblum JH, Mckerrow M, Banda J . 1990 Cancer Res. 50: 2322–2329

  • Barillé SC, Akhoundi M, Collette MP, Mellerin MJ, Rapp JL, Harousseau R, Bataille M, Aminot M . 1997 Blood. 90: 1649–1655

  • Bjerkvig R, Laerum OD, Mella O . 1986 Cancer Res. 46: 407–409

  • Bian J, Sun Y . 1997 Mol. Cell. Biol. 17: 6330–6338

  • Cairns P, Okami K, Halachmi S, Halachm N, Esteller M, Herman JG, Jen J, Isaacs WB, Bova GS, Sidransky D . 1997 Cancer Res. 57: 4997–5000

  • Cheney IW, Johnson DE, Vaillancourt MT, Avanzini J, Morimoto A, Demers GW, Wills KN, Shabram PW, Bolen JB, Tavtigian SV, Brookstein R . 1999 Cancer Res. 58: 2331–2334

  • Chintala SK, Sawaya R, Gokaslan ZL, Rao JS . 1996 Cancer Lett. 103: 201–208

  • Chintala SK, Rao JK . 1996 Front Bioscience 1: 324–339

  • Cockett MI, Birch ML, Murphy G, Hart IR, Docherty AJ . 1994 Biochem. Soc. Trans. 22: 55–57

  • Davies B, Waxman J, Wasan H, Abel P, Williams G, Krausz T, Neal D, Thomas D, Hanby A, Balkwill F . 1993 Cancer Res. 22: 5365–5369

  • Davies MA, Lu Y, Sano T, Fang X, Tang P, LaPushin R, Koul D, Bookstein R, Stokoe D, Yung WK, Mills GB, Steck PA . 1998 Cancer Res. 58: 5285–5290

  • Deryugina EI, Luo GX, Reisfeld RA, Bourdon MA, Strongin A . 1997 Anticancer Res. 17: 3201–3210

  • Di Cristofano A, Pesce B, Cordon-Cardo C, Pandolfi PP . 1998 Nat. Genet. 19: 348–355

  • Edwards DR, Beaudry PP, Laing TD, Kowal V, Leco KJ, Leco PA, Lim MS . 1996 Int. J. Obes. Relat. Metab. Disord. 20: Suppl 3 S9–S15

  • Fang J, Shing Y, Wiederschain D, Yan L, Butterfield C, Jackson G, Harper J, Tamvakopoulos G, Moses MA . 2000 Proc. Natl. Acad. Sci. USA 97: 3884–3889

  • Frisch SM, Francis H . 1994 J. Cell Biol. 124: 619–626

  • Furnari FB, Huang HJ, Cavenee WK . 1998 Cancer Res. 58: 5002–5008

  • Furnari FB, Lin H, Huang HJ, Cavenee WK . 1997 Proc. Natl. Acad. Sci. USA 94: 12479–12484

  • Guldberg P, Thor Straten P, Birck A, Ahrenkiel V, Kirkin AF, Zeuthen J . 1997 Cancer Res. 57: 3660–3663

  • Himelstein BP, Canete-Soler EJ, Bernhard DW, Dilks RJ, Muschel R . 1995 Invasion Metastasis. 14: 246–258

  • Kim H, Koh G . 2000 Biochem. Biophys. Res. Commun. 269: 401–405

  • Koul D, Yao Y, Abbruzzese JL, Yung WK, Reddy SA . 2001 J. Biol. Chem. 276: 11402–11408

  • Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigne S, Giovanell BC, Ittmann M, Tycko B, Hibshoosh H, Wigler M, Parsons R . 1997 Science. 275: 1943–1947

  • Li DM, Sun H . 1998 Proc. Natl. Acad. Sci. USA. 22: 15406–15411

  • Liaw D, Marsh DJ, Li J, Dahia PL, Wang SI, Zheng Z, Bose S, Call KM, Tsou HC, Peacock M, Eng C, Parsons R . 1997 Nat. Genet. 16: 64–67

  • Lu Y, Lin YZ, LaPushin R, Cuevas B, Fang X, Yu SX, Davies MA, Khan H, Furui T, Mao M, Zinner R, Hung MC, Steck P, Siminovitch K, Mills GB . 1999 Oncogene. 18: 7034–7045

  • Maehama T, Dixon JE . 1998 J. Biol. Chem. 273: 13375–13378

  • Maier D, Jones G, Li X, Schonthal AH, Gratzl O, Van Meir EG, Merlo A . 1999 Cancer Res. 21: 5479–5482

  • Marsh DJ, Dahia PL, Zheng Z, Liaw D, Parsons R, Gorlin RJ, Eng C . 1997 Nat. Genet. 16: 333–334

  • Meyers MP, Stolarov JP, Eng C, Li J, Wang SI, Wigler MH, Parson R, Tonks NK . 1997 Proc. Natl. Acad. Sci. USA 94: 9052–9057

  • Mignatti P, Rifkin DB . 1993 Physiol Rev. 73: 161–195

  • Mohanam S, Sawaya R, McCutcheon I, Ali-Osman F, Boyd D, Rao JS . 1993 Cancer Res. 53: 4143–4147

  • Morimoto AM, Berson AE, Fujii GH, Teng DH, Tavtigian SV, Bookstein R, Steck PA, Bolen JB . 1999 Oncogene 11: 1261–1266

  • Moscatelli D, Rifkin DB . 1988 Biochim. Biophys. Acta 948: 67–85

  • Moser TL, Young TN, Rodriguez GC, Pizzo SV, Bast Jr RC, Stack MS . 1994 Int. J. Cancer 56: 552–559

  • Nakajima M, Welch DR, Wynn DM, Tsuruo T, Nicolson GL . 1993 Cancer Res. 23: 5802–5807

  • Nakano AE, Tani K, Miyazaki Y, Yamamoto JI, Furuyama I . 1995 J. Neurosurg. 83: 298–307

  • Qin H, Moellinger JD, Wells A, Windsor LJ, Sun Y, Benveniste EN . 1998 J. Immunol. 12: 6664–6673

  • Rao JS, Steck PA, Tofilon P, Boyd D, Ali-Osman F, Stetler-Stevenson WG, Liotta LA, Sawaya R . 1994 J. Neurooncol. 18: 129–138

  • Rhei E, Kang L, Bogomolniy F, Federici MG, Borgen PI, Boyd J . 1997 Cancer Res. 57: 3657–3659

  • Rucklidge GJ, Edvardsen K, Bock E . 1994 Biochem. Soc. Trans. 22: 63–68

  • Sato H, Kida Y, Mai M, Endo Y, Sasaki T, Tanaka J, Seiki M . 1992 Oncogene 7: 77–83

  • Sato H, Takino T, Okada Y, Cao J, Shinagawa A, Yamamoto E, Seiki M . 1994 Nature 370: 61–65

  • Seftor RE, Seftor EA, Stetler-Stevenson WG, Hendrix MJ . 1993 Cancer Res. 53: 3411–3415

  • Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, Ruland J, Penninger JM, Siderovski DP, Mak TW . 1998 Cell 95: 29–39

  • Steck PA, Perhouse MA, Jasser SA, Yung WKA, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng DHF, Tavtigian SV . 1997 Nat. Genet. 15: 356–362

  • Stetler-Stevenson WG, Hewitt R, Corcoran M . 1996 Semin. Cancer Biol. 7: 147–154

  • Tamura M, Gu J, Matsumoto K, Aota S, Parsons R, Yamada KM . 1998 Science 280: 1614–1617

  • Tamura M, Gu J, Danen EH, Takino T, Miyamoto S, Yamada KM . 1999 J. Biol. Chem. 274: 20693–20703

  • Tashiro H, Blazes MS, Wu R, Cho KR, Bose S, Wang SI, Li J, Parsons R, Ellenson LH . 1997 Cancer Res. 57: 3935–3940

  • Tian XX, Pang JC, To SS, Ng HK . 1999 J. Neuropathol. Exp. Neurol. 58: 472–479

  • Uhm JH, Dooley NP, Villemure JG, Yong VW . 1997 Can. J. Neuro. Sci. 24: 3–15

  • Uhm JH, Dooley NP, Villemure JG, Yong VW . 1996 Clin. Exp. Metastasis 14: 421–433

  • Vassalli JD, Pepper MS . 1994 Nature 370: 14–15

  • Wang SI, Puc J, Li J, Bruce JN, Cairns P, Sidransky D, Parsons R . 1997 Cancer Res. 57: 4183–4186

  • Xuan JW, Tuck AB, Wilson SM, Chin Jl, Chambers AF . 1998 Anticancer Res. 18: 743–749

  • Yong VW, Krekoski CA, Forsyth PA, Bell R, Edwards DR . 1998 Trends Neurosci. 21: 75–80

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Acknowledgements

This work was supported by grants RO1 CA 51148 to WKA Yung from the National Institute of Health, a grant from the Gilland Foundation to WKA Yung; and Cancer Center Core Grant, CA16672.

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Authors and Affiliations

  1. Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, Texas, USA

    Dimpy Koul, Ranjani Parthasarathy, Ruijun Shen, Michael A Davies, Samar A Jasser, Ta-Jen Liu & W K Alfred Yung

  2. Department of Neuro-Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, Texas, USA

    Shravan K Chintala & Jasti S Rao

  3. Department of Molecular Biology, Parke-Davis Pharmaceutical Research, Ann Arbor, MI 48105, Michigan, USA

    Yi Sun

  4. Department of Cell Biology, University of Alabama, Birmingham, AL 35294, Alabama, USA

    Etty N Benvenisite

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  1. Dimpy Koul
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Correspondence to W K Alfred Yung.

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Koul, D., Parthasarathy, R., Shen, R. et al. Suppression of matrix metalloproteinase-2 gene expression and invasion in human glioma cells by MMAC/PTEN. Oncogene 20, 6669–6678 (2001). https://doi.org/10.1038/sj.onc.1204799

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