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Inhibition of apoptosis in human tumour cells by the tumour-associated serpin, SCC antigen-1
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  • Published: 20 January 2000

Inhibition of apoptosis in human tumour cells by the tumour-associated serpin, SCC antigen-1

  • Y Suminami1,2,
  • S Nagashima1,
  • N L Vujanovic1,
  • K Hirabayashi2,
  • H Kato2 &
  • …
  • T L Whiteside1,3 

British Journal of Cancer volume 82, pages 981–989 (2000)Cite this article

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Abstract

The squamous cell carcinoma antigen (SCC Ag) is a tumour-associated protein and a member of theserineproteaseinhibitor (serpin) family. The SCC Ag has been used as a serologic tumour marker for SCC progression, and its elevated serum levels are a risk factor for disease relapse. However, the biologic significance of this intracytoplasmic protein in cancer cells remains unknown. In this report, we demonstrated that apoptosis induced by 7-ethyl-10-hydroxycamptothecin, tumour necrosis factor-α (TNF-α) or interleukin (IL)-2-activated natural killer (NK) cells was significantly inhibited in tumour cells transduced with the SCC Ag-1 cDNA, as compared to control cells in vitro. Also, inhibition of the SCC Ag-1 expression in tumour cells by transfection of antisense SCC Ag-1 cDNA was accompanied by significantly increased sensitivity of these cells to apoptosis induced by etoposide or TNF-α. The mechanism of protection of tumour cells from apoptosis involved inhibition of caspase-3 activity and/or upstream proteases. In vivo, tumour cells overexpressing the SCC Ag-1 formed significantly larger tumours in nude mice than the SCC Ag-1-negative controls. Thus, overexpression of the SCC Ag-1, a member of the serpin family, in human cancer cells contributed to their survival by mediating protection from drug-, cytokine- or effector cell-induced apoptosis. © 2000 Cancer Research Campaign

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  • 16 November 2011

    This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication

References

  • Alnemri ES, Livingston DJ, Nicholson DW, Salvesen G, Thornberry NA, Wong WW and Yuan J (1996) Human ICE/CED-3 protease nomenclature [letter]. Cell 87: 171

    Article  CAS  PubMed  Google Scholar 

  • Belin D, Wohlwend A, Schleuning WD, Kruithof EK and Vassalli JD (1989) Facultative polypeptide translocation allows a single mRNA to encode the secreted and cytosolic forms of plasminogen activators inhibitor 2. EMBO J 8: 3287–3294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bouchet C, Spyratos F, Martin PM, Hacene K, Gentile A and Oglobine J (1994) Prognostic value of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitors PAI-1 and PAI-2 in breast carcinomas. Br J Cancer 69: 398–405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheng EH, Kirsch DG, Clem RJ, Ravi R, Kastan MB, Bedi A, Ueno K and Hardwick JM (1997) Conversion of Bcl-2 to a Bax-like death effector by caspases. Science 278: 1966–1968

    Article  CAS  PubMed  Google Scholar 

  • Danos O and Mulligan RC (1988) Safe and efficient generation of recombinant retroviruses with amphotropic and ecotropic host ranges. Proc Natl Acad Sci USA 85: 6460–6464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Datta R, Kojima H, Banach D, Bump NJ, Talanian RV, Alnemri ES, Weichselbaum RR, Wong WW and Kufe DW (1997) Activation of a CrmA-insensitive, p35-sensitive pathway in ionizing radiation-induced apoptosis. J Biol Chem 272: 1965–1969

    Article  CAS  PubMed  Google Scholar 

  • de Vries TJ, Quax PH, Denijn M, Verrijp KN, Verheijen JH, Verspaget HW, Weidle UH, Ruiter DJ and van Muijen GN (1994) Plasminogen activators, their inhibitors, and urokinase receptor emerge in late stages of melanocytic tumour progression. Am J Pathol 144: 70–81

    CAS  PubMed  PubMed Central  Google Scholar 

  • Desjardins LM and MacManus JP (1995) An adherent cell model to study different stages of apoptosis. Exp Cell Res 216: 380–387

    Article  CAS  PubMed  Google Scholar 

  • Dickinson JL, Bates EJ, Ferrante A and Antalis TM (1995) Plasminogen activator inhibitor type 2 inhibits tumour necrosis factor alpha-induced apoptosis. Evidence for an alternate biological function. J Biol Chem 270: 27894–27904

    Article  CAS  PubMed  Google Scholar 

  • Duk JM, Groenier KH, de Bruijn HW, Hollema H, ten Hoor KA, van der Zee AG and Aalders JG (1996) Pretreatment serum squamous cell carcinoma antigen: a newly identified prognostic factor in early-stage cervical carcinoma. J Clin Oncol 14: 111–118

    Article  CAS  PubMed  Google Scholar 

  • Enari M, Hug H and Nagata S (1995) Involvement of an ICE-like protease in Fas-mediated apoptosis. Nature 375: 78–81

    Article  CAS  PubMed  Google Scholar 

  • Fisher DE (1994) Apoptosis in cancer therapy: crossing the threshold. [Review]. Cell 78: 539–542

    Article  CAS  PubMed  Google Scholar 

  • Foekens JA, Buessecker F, Peters HA, Krainick U, van Putten WL, Look MP, Klijn JG and Kramer MD (1995) Plasminogen activator inhibitor-2: prognostic relevance in 1012 patients with primary breast cancer. Cancer Res 55: 1423–1427

    CAS  PubMed  Google Scholar 

  • Fontanini G, Vignati S, Bigini D, Mussi A, Lucchi M, Angeletti CA, Basolo F and Bevilacqua G (1995) Bcl-2 protein: a prognostic factor inversely correlated to p53 in non-small-cell lung cancer. Br J Cancer 71: 1003–1007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gan H, Newman GW and Remold HG (1995) Plasminogen activator inhibitor type 2 prevents programmed cell death of human macrophages infected with Mycobacterium avium, serovar 4. J Immunol 155: 1304–1315

    CAS  PubMed  Google Scholar 

  • Herod JJ, Eliopoulos AG, Warwick J, Niedobitek G, Young LS and Kerr DJ (1996) The prognostic significance of Bcl-2 and p53 expression in ovarian carcinoma. Cancer Res 56: 2178–2184

    CAS  PubMed  Google Scholar 

  • Hirabayashi H, Yasumura S, Lin WC, Amoscato A, Johnson JT, Herberman RB and Whiteside TL (1995) Production by human squamous cell carcinoma of a factor inducing activation and proliferation of immune cells. Arch Otolaryngol Head Neck Surg 121: 285–292

    Article  CAS  PubMed  Google Scholar 

  • Hu Y, Benedict MA, Wu D, Inohara N and Nunez G (1998) Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation. Proc Natl Acad Sci USA 95: 4386–4391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kato H (1992) Squamous cell carcinoma antigen. Serological Cancer Markers, Sell S (ed), pp. 437–451, Humana Press: Clifton

    Chapter  Google Scholar 

  • Kato H and Torigoe T (1977) Radioimmunoassay for tumour antigen of human cervical squamous cell carcinoma. Cancer 40: 1621–1628

    Article  CAS  PubMed  Google Scholar 

  • Kato H, Miyauchi F, Morioka H, Fujino T and Torigoe T (1979) Tumor antigen of human cervical squamous cell carcinoma: correlation of circulating levels with disease progress. Cancer 43: 585–590

    Article  CAS  PubMed  Google Scholar 

  • Kato H, Nagaya T and Torigoe T (1984) Heterogeneity of a tumour antigen TA-4 of squamous cell carcinoma in relation to its appearance in the circulation. Gann 75: 433–435

    CAS  PubMed  Google Scholar 

  • Mino N, Iio A and Hamamoto K (1988) Availability of tumour-antigen 4 as a marker of squamous cell carcinoma of the lung and other organs. Cancer 62: 730–734

    Article  CAS  PubMed  Google Scholar 

  • Miyashita T and Reed JC (1993) Bcl-2 oncoprotein blocks chemotherapy-induced apoptosis in a human leukemia cell line. Blood 81: 151–157

    CAS  PubMed  Google Scholar 

  • Nagashima S, Kashii Y, Reichert TE, Suminami Y, Suzuki T and Whiteside TL (1997) Human gastric carcinoma transduced with the IL-2 gene: increased sensitivity to immune effector cells in vitro and in vivo. Int J Cancer 72: 174–183

    Article  CAS  PubMed  Google Scholar 

  • Nagayama M, Sato A, Hayakawa H, Urano T, Takada Y and Takada A (1994) Plasminogen activators and their inhibitors in non-small cell lung cancer. Low content of type 2 plasminogen activator inhibitor associated with tumour dissemination. Cancer 73: 1398–1405

    Article  CAS  PubMed  Google Scholar 

  • Nakanishi H, Ohsawa M, Naka N, Uchida A, Ochi T and Aozasa K (1997) Immunohistochemical detection of bcl-2 and p53 proteins and apoptosis in soft tissue sarcoma: their correlations with prognosis. Oncology 54: 238–244

    Article  CAS  PubMed  Google Scholar 

  • Nakatsu S, Kondo S, Kondo Y, Yin D, Peterson JW, Kaakaji R, Morimura T, Kikuchi H, Takeuchi J and Barnett GH (1997) Induction of apoptosis in multidrug resistant (MDR) human glioblastoma cells by SN-38, a metabolite of the camptothecin derivative CPT-11. Cancer Chemother Pharmacol 39: 417–423

    Article  CAS  PubMed  Google Scholar 

  • Nawata S, Tsunaga N, Numa F, Tanaka T, Nakamura K and Kato H (1995) Serine protease inhibitor activity of recombinant squamous cell carcinoma antigen towards chymotrypsin, as demonstrated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Electrophoresis 16: 1027–1030

    Article  CAS  PubMed  Google Scholar 

  • Nawata S, Nakamura K, Tanaka T, Numa F, Suminami Y, Tsunaga N, Kakegawa H, Katunuma N and Kato H (1997) Electrophoretic analysis of the ‘cross-class’ interaction between novel inhibitory serpin, squamous cell carcinoma antigen-1 and cysteine proteinases. Electrophoresis 18: 784–789

    Article  CAS  PubMed  Google Scholar 

  • Numa F, Takeda O, Nakata M, Nawata S, Tsunaga N, Hirabayashi K, Suminami Y, Kato H and Hamanaka S (1996) Tumour necrosis factor-α stimulates the production of pquamous cell carcinoma antigen in normal squamous cells. Tumour Biol 17: 97–101

    Article  CAS  PubMed  Google Scholar 

  • Ohashi T, Boggs S, Robbins P, Bahnson A, Patrene K, Wei FS, Wei JF, Li J, Lucht L and Fei Y (1992) Efficient transfer and sustained high expression of the human glucocerebrosidase gene in mice and their functional macrophages following transplantation of bone marrow transduced by a retroviral vector. Proc Natl Acad Sci USA 89: 11332–11336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ohmori T, Podack ER, Nishio K, Takahashi M, Miyahara Y, Takeda Y, Kubota N, Funayama Y, Ogasawara H and Ohira T (1993) Apoptosis of lung cancer cells caused by some anti-cancer agents (MMC, CPT-11, ADM) is inhibited by bcl-2. Biochem Biophys Res Commun 192: 30–36

    Article  CAS  PubMed  Google Scholar 

  • Ormerod MG, O’Neill CF, Robertson D and Harrap KR (1994) Cisplatin induces apoptosis in a human ovarian carcinoma cell line without concomitant internucleosomal degradation of DNA. Exp Cell Res 211: 231–237

    Article  CAS  PubMed  Google Scholar 

  • Pan G, O’Rourke K and Dixit VM (1998) Caspase-9, Bcl-XL, and Apaf-1 form a ternary complex. J Biol Chem 273: 5841–5845

    Article  CAS  PubMed  Google Scholar 

  • Potempa J, Korzus E and Travis J (1994) The serpin superfamily of proteinase inhibitors: structure, function, and regulation. [Review]. J Biol Chem 269: 15957–15960

    CAS  PubMed  Google Scholar 

  • Pross HF, Baines MG, Rubin P, Shragge P and Patterson MS (1981) Spontaneous human lymphocyte-mediated cytotoxicity against tumour target cells. IX. The quantitation of natural killer cell activity. J Clin Immunol 1: 51–63

    Article  CAS  PubMed  Google Scholar 

  • Reed JC (1995) Regulation of apoptosis by bcl-2 family proteins and its role in cancer and chemoresistance. [Review]. Curr Opin Oncol 7: 541–546

    Article  CAS  PubMed  Google Scholar 

  • Reed JC (1997) Double identity for proteins of the Bcl-2 family. [Review]. Nature 387: 773–776

    Article  CAS  PubMed  Google Scholar 

  • Scherrer A, Kruithof EK and Grob JP (1991) Plasminogen activator inhibitor-2 in patients with monocytic leukemia. Leukemia 5: 479–486

    CAS  PubMed  Google Scholar 

  • Schneider SS, Schick C, Fish KE, Miller E, Pena JC, Treter SD, Hui SM and Silverman GA (1995) A serine proteinase inhibitor locus at 18q21.3 contains a tandem duplication of the human squamous cell carcinoma antigen gene. Proc Natl Acad Sci USA 92: 3147–3151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Suminami Y, Kishi F, Sekiguchi K and Kato H (1991) Squamous cell carcinoma antigen is a new member of the serine protease inhibitors. Biochem Biophys Res Commun 181: 51–58

    Article  CAS  PubMed  Google Scholar 

  • Sumiyoshi K, Serizawa K, Urano T, Takada Y, Takada A and Baba S (1992) Plasminogen activator system in human breast cancer. Int J Cancer 50: 345–348

    Article  CAS  PubMed  Google Scholar 

  • Takeda A, Yamamoto T, Nakamura Y, Takahashi T and Hibino T (1995) Squamous cell carcinoma antigen is a potent inhibitor of cysteine proteinase cathepsin L. FEBS Lett 359: 78–80

    Article  CAS  PubMed  Google Scholar 

  • Takeshima N, Nakamura K, Takeda O, Morioka H, Tamura H, Takasugi N and Kato H (1990) Individualization of the cutoff value for serum squamous-cell carcinoma antigen using a sensitive enzyme immunoassay. Tumour Biol 11: 167–172

    Article  CAS  PubMed  Google Scholar 

  • Tewari M and Dixit VM (1995) Fas- and tumor necrosis factor-induced apoptosis is inhibited by the poxvirus crmA gene product. J Biol Chem 270: 3255–3260

    Article  CAS  PubMed  Google Scholar 

  • Tewari M, Quan LT, O’Rourke K, Desnoyers S, Zeng Z, Beidler DR, Poirier GG, Salvesen GS and Dixit VM (1995 a) Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly (ADP-ribose) polymerase. Cell 81: 801–809

    Article  CAS  PubMed  Google Scholar 

  • Tewari M, Telford WG, Miller RA and Dixit VM (1995 b) CrmA, a poxvirus-encoded serpin, inhibits cytotoxic T-lymphocyte-mediated apoptosis. J Biol Chem 270: 22705–22708

    Article  CAS  PubMed  Google Scholar 

  • Vujanovic NL, Rabinowich H, Lee YJ, Jost L, Herberman RB and Whiteside TL (1993) Distinct phenotypic and functional characteristics of human natural killer cells obtained by rapid interleukin 2-induced adherence to plastic. Cell Immunol 151: 133–157

    Article  PubMed  Google Scholar 

  • Vujanovic NL, Nagashima S, Giorda R, Herberman RB and Whiteside TL (1995 a) Multiple mechanisms of killing of tumour cell targets by IL-2-activated natural killer cells. Abstract Book of the 9th International Congress of Immunology (San Francisco, CA), 486(2883)

  • Vujanovic NL, Yasumura S, Hirabayashi H, Lin WC, Watkins S, Herberman RB and Whiteside TL (1995 b) Antitumour activities of subsets of human IL-2-activated natural killer cells in solid tissues. J Immunol 154: 281–289

    CAS  PubMed  Google Scholar 

  • Vujanovic NL, Nagashima S, Herberman RB and Whiteside TL (1996) Non-secretory apoptotic killing by human NK cells. J Immunol 157: 1117–1126

    CAS  PubMed  Google Scholar 

  • Yoshida A, Ueda T, Wano Y and Nakamura T (1993) DNA damage and cell killing by camptothecin and its derivative in human leukemia HL-60 cells. Jpn J Cancer Res 84: 566–573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zitvogel L, Tahara H, Cai Q, Storkus WJ, Muller G, Wolf SF, Gately M, Robbins PD and Lotze MT (1994) Construction and characterization of retroviral vectors expressing biologically active human interleukin-12. Hum Gene Ther 5: 1493–1506

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. University of Pittsburgh Cancer Institute, 200 Lothrop Street, W1041 BST, Pittsburgh, 15213, PA, USA

    Y Suminami, S Nagashima, N L Vujanovic & T L Whiteside

  2. Department of Pathology and Otolaryngology, University of Pittsburgh School of Medicine, 200 Lothrop Street, W1041 BST, Pittsburgh, 15213, PA, USA

    Y Suminami, K Hirabayashi & H Kato

  3. Department of Obstetrics and Gynecology, Yamaguchi University School of Medicine, 755-8505, Ube, Japan

    T L Whiteside

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From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

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Suminami, Y., Nagashima, S., Vujanovic, N. et al. Inhibition of apoptosis in human tumour cells by the tumour-associated serpin, SCC antigen-1. Br J Cancer 82, 981–989 (2000). https://doi.org/10.1054/bjoc.1999.1028

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  • Received: 09 March 1999

  • Revised: 29 July 1999

  • Accepted: 05 August 1999

  • Published: 20 January 2000

  • Issue date: 01 February 2000

  • DOI: https://doi.org/10.1054/bjoc.1999.1028

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Keywords

  • tumour-associated protein
  • serpin
  • SCC Ag-1
  • apoptosis
  • protection from apoptosis

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