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
Similar content being viewed by others
Article PDF
Change history
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
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
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
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
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
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
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
Desjardins LM and MacManus JP (1995) An adherent cell model to study different stages of apoptosis. Exp Cell Res 216: 380–387
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
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
Enari M, Hug H and Nagata S (1995) Involvement of an ICE-like protease in Fas-mediated apoptosis. Nature 375: 78–81
Fisher DE (1994) Apoptosis in cancer therapy: crossing the threshold. [Review]. Cell 78: 539–542
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
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
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
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
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
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
Kato H (1992) Squamous cell carcinoma antigen. Serological Cancer Markers, Sell S (ed), pp. 437–451, Humana Press: Clifton
Kato H and Torigoe T (1977) Radioimmunoassay for tumour antigen of human cervical squamous cell carcinoma. Cancer 40: 1621–1628
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
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
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
Miyashita T and Reed JC (1993) Bcl-2 oncoprotein blocks chemotherapy-induced apoptosis in a human leukemia cell line. Blood 81: 151–157
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Reed JC (1997) Double identity for proteins of the Bcl-2 family. [Review]. Nature 387: 773–776
Scherrer A, Kruithof EK and Grob JP (1991) Plasminogen activator inhibitor-2 in patients with monocytic leukemia. Leukemia 5: 479–486
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
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
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
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
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
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
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
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
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
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
Vujanovic NL, Nagashima S, Herberman RB and Whiteside TL (1996) Non-secretory apoptotic killing by human NK cells. J Immunol 157: 1117–1126
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
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
Author information
Authors and Affiliations
Rights and permissions
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/
About this article
Cite this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1054/bjoc.1999.1028
Keywords
This article is cited by
-
Loss of epidermal MCPIP1 is associated with aggressive squamous cell carcinoma
Journal of Experimental & Clinical Cancer Research (2021)
-
Serum squamous cell carcinoma antigen as an early indicator of response during therapy of cervical cancer
British Journal of Cancer (2018)
-
SERPINB3/B4 Contributes to Early Inflammation and Barrier Dysfunction in an Experimental Murine Model of Atopic Dermatitis
Journal of Investigative Dermatology (2015)
-
Hepatic progenitor cells express SerpinB3
BMC Cell Biology (2014)
-
Oncogenic Ras induces inflammatory cytokine production by upregulating the squamous cell carcinoma antigens SerpinB3/B4
Nature Communications (2014)