Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2001 Mar;84(6):851–858. doi: 10.1054/bjoc.2000.1683

Squamous cell carcinoma antigen suppresses radiation-induced cell death

A Murakami 1,2, Y Suminami 1, H Hirakawa 1, S Nawata 1, F Numa 1, H Kato 1
PMCID: PMC2363809  PMID: 11259103

Abstract

Previous study has demonstrated that squamous cell carcinoma antigen (SCCA) 1 attenuates apoptosis induced by TNFα, NK cell or anticancer drug. In this study, we have examined the effect of SCCA2, which is highly homologous to SCCA1, but has different target specificity, against radiation-induced apoptosis, together with that of SCCA1. We demonstrated that cell death induced by radiation treatment was remarkably suppressed not only in SCCA1 cDNA-transfected cells, but also in SCCA2 cDNA-transfected cells. In these transfectants, caspase 3 activity and the expression of activated caspase 9 after radiation treatment were suppressed. Furthermore, the expression level of phosphorylated p38 mitogen-activated protein kinase (p38 MAPK) was suppressed compared to that of the control cells. The expression level of upstream stimulator of p38 MAPK, phosphorylated MKK3/MKK6, was also suppressed in the radiation-treated cells. Thus, both SCCA1 and SCCA2 may contribute to survival of the squamous cells from radiation-induced apoptosis by regulating p38 MAPK pathway. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords: SCCA, apoptosis, radiation, caspase 3 activity, caspase 9, p38 MAPK

Full Text

The Full Text of this article is available as a PDF (235.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alnemri E. S., Livingston D. J., Nicholson D. W., Salvesen G., Thornberry N. A., Wong W. W., Yuan J. Human ICE/CED-3 protease nomenclature. Cell. 1996 Oct 18;87(2):171–171. doi: 10.1016/s0092-8674(00)81334-3. [DOI] [PubMed] [Google Scholar]
  2. Belin D., Wohlwend A., Schleuning W. D., Kruithof E. K., Vassalli J. D. Facultative polypeptide translocation allows a single mRNA to encode the secreted and cytosolic forms of plasminogen activators inhibitor 2. EMBO J. 1989 Nov;8(11):3287–3294. doi: 10.1002/j.1460-2075.1989.tb08489.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bird C. H., Sutton V. R., Sun J., Hirst C. E., Novak A., Kumar S., Trapani J. A., Bird P. I. Selective regulation of apoptosis: the cytotoxic lymphocyte serpin proteinase inhibitor 9 protects against granzyme B-mediated apoptosis without perturbing the Fas cell death pathway. Mol Cell Biol. 1998 Nov;18(11):6387–6398. doi: 10.1128/mcb.18.11.6387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bird P. I. Regulation of pro-apoptotic leucocyte granule serine proteinases by intracellular serpins. Immunol Cell Biol. 1999 Feb;77(1):47–57. doi: 10.1046/j.1440-1711.1999.00787.x. [DOI] [PubMed] [Google Scholar]
  5. Brenner B., Koppenhoefer U., Weinstock C., Linderkamp O., Lang F., Gulbins E. Fas- or ceramide-induced apoptosis is mediated by a Rac1-regulated activation of Jun N-terminal kinase/p38 kinases and GADD153. J Biol Chem. 1997 Aug 29;272(35):22173–22181. doi: 10.1074/jbc.272.35.22173. [DOI] [PubMed] [Google Scholar]
  6. Brioschi P. A., Bischof P., Delafosse C., Krauer F. Squamous-cell carcinoma antigen (SCC-A) values related to clinical outcome of pre-invasive and invasive cervical carcinoma. Int J Cancer. 1991 Feb 1;47(3):376–379. doi: 10.1002/ijc.2910470311. [DOI] [PubMed] [Google Scholar]
  7. Chen Y. R., Meyer C. F., Tan T. H. Persistent activation of c-Jun N-terminal kinase 1 (JNK1) in gamma radiation-induced apoptosis. J Biol Chem. 1996 Jan 12;271(2):631–634. doi: 10.1074/jbc.271.2.631. [DOI] [PubMed] [Google Scholar]
  8. Chen Y. R., Wang X., Templeton D., Davis R. J., Tan T. H. The role of c-Jun N-terminal kinase (JNK) in apoptosis induced by ultraviolet C and gamma radiation. Duration of JNK activation may determine cell death and proliferation. J Biol Chem. 1996 Dec 13;271(50):31929–31936. doi: 10.1074/jbc.271.50.31929. [DOI] [PubMed] [Google Scholar]
  9. Chen Z., Seimiya H., Naito M., Mashima T., Kizaki A., Dan S., Imaizumi M., Ichijo H., Miyazono K., Tsuruo T. ASK1 mediates apoptotic cell death induced by genotoxic stress. Oncogene. 1999 Jan 7;18(1):173–180. doi: 10.1038/sj.onc.1202276. [DOI] [PubMed] [Google Scholar]
  10. Cobb M. H., Goldsmith E. J. How MAP kinases are regulated. J Biol Chem. 1995 Jun 23;270(25):14843–14846. doi: 10.1074/jbc.270.25.14843. [DOI] [PubMed] [Google Scholar]
  11. Cohen G. M. Caspases: the executioners of apoptosis. Biochem J. 1997 Aug 15;326(Pt 1):1–16. doi: 10.1042/bj3260001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Dickens M., Rogers J. S., Cavanagh J., Raitano A., Xia Z., Halpern J. R., Greenberg M. E., Sawyers C. L., Davis R. J. A cytoplasmic inhibitor of the JNK signal transduction pathway. Science. 1997 Aug 1;277(5326):693–696. doi: 10.1126/science.277.5326.693. [DOI] [PubMed] [Google Scholar]
  13. Enari M., Hug H., Nagata S. Involvement of an ICE-like protease in Fas-mediated apoptosis. Nature. 1995 May 4;375(6526):78–81. doi: 10.1038/375078a0. [DOI] [PubMed] [Google Scholar]
  14. Furuya Y., Krajewski S., Epstein J. I., Reed J. C., Isaacs J. T. Expression of bcl-2 and the progression of human and rodent prostatic cancers. Clin Cancer Res. 1996 Feb;2(2):389–398. [PubMed] [Google Scholar]
  15. Guo Y. L., Baysal K., Kang B., Yang L. J., Williamson J. R. Correlation between sustained c-Jun N-terminal protein kinase activation and apoptosis induced by tumor necrosis factor-alpha in rat mesangial cells. J Biol Chem. 1998 Feb 13;273(7):4027–4034. doi: 10.1074/jbc.273.7.4027. [DOI] [PubMed] [Google Scholar]
  16. Hakem R., Hakem A., Duncan G. S., Henderson J. T., Woo M., Soengas M. S., Elia A., de la Pompa J. L., Kagi D., Khoo W. Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell. 1998 Aug 7;94(3):339–352. doi: 10.1016/s0092-8674(00)81477-4. [DOI] [PubMed] [Google Scholar]
  17. Hibi M., Lin A., Smeal T., Minden A., Karin M. Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes Dev. 1993 Nov;7(11):2135–2148. doi: 10.1101/gad.7.11.2135. [DOI] [PubMed] [Google Scholar]
  18. Huang Y., Sheikh M. S., Fornace A. J., Jr, Holbrook N. J. Serine protease inhibitor TPCK prevents Taxol-induced cell death and blocks c-Raf-1 and Bcl-2 phosphorylation in human breast carcinoma cells. Oncogene. 1999 Jun 10;18(23):3431–3439. doi: 10.1038/sj.onc.1202685. [DOI] [PubMed] [Google Scholar]
  19. Hunter T. Oncoprotein networks. Cell. 1997 Feb 7;88(3):333–346. doi: 10.1016/s0092-8674(00)81872-3. [DOI] [PubMed] [Google Scholar]
  20. Karin M. The regulation of AP-1 activity by mitogen-activated protein kinases. J Biol Chem. 1995 Jul 14;270(28):16483–16486. doi: 10.1074/jbc.270.28.16483. [DOI] [PubMed] [Google Scholar]
  21. Kato H., Morioka H., Aramaki S., Tamai K., Torigoe T. Prognostic significance of the tumor antigen TA-4 in squamous cell carcinoma of the uterine cervix. Am J Obstet Gynecol. 1983 Feb 1;145(3):350–354. doi: 10.1016/0002-9378(83)90723-8. [DOI] [PubMed] [Google Scholar]
  22. Kato H., Morioka H., Tsutsui H., Aramaki S., Torigoe T. Value of tumor-antigen (TA-4) of squamous cell carcinoma in predicting the extent of cervical cancer. Cancer. 1982 Oct 1;50(7):1294–1296. doi: 10.1002/1097-0142(19821001)50:7<1294::aid-cncr2820500712>3.0.co;2-k. [DOI] [PubMed] [Google Scholar]
  23. Kato H., Nagaya T., Torigoe T. Heterogeneity of a tumor antigen TA-4 of squamous cell carcinoma in relation to its appearance in the circulation. Gan. 1984 May;75(5):433–435. [PubMed] [Google Scholar]
  24. Kato H., Torigoe T. Radioimmunoassay for tumor antigen of human cervical squamous cell carcinoma. Cancer. 1977 Oct;40(4):1621–1628. doi: 10.1002/1097-0142(197710)40:4<1621::aid-cncr2820400435>3.0.co;2-i. [DOI] [PubMed] [Google Scholar]
  25. Kerr J. F., Wyllie A. H., Currie A. R. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972 Aug;26(4):239–257. doi: 10.1038/bjc.1972.33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Krajewska M., Krajewski S., Epstein J. I., Shabaik A., Sauvageot J., Song K., Kitada S., Reed J. C. Immunohistochemical analysis of bcl-2, bax, bcl-X, and mcl-1 expression in prostate cancers. Am J Pathol. 1996 May;148(5):1567–1576. [PMC free article] [PubMed] [Google Scholar]
  27. Kuwano A., Kondo I., Kishi F., Suminami Y., Kato H. Assignment of the squamous cell carcinoma antigen locus (SCC) to 18q21 by in situ hybridization. Genomics. 1995 Dec 10;30(3):626–626. doi: 10.1006/geno.1995.1290. [DOI] [PubMed] [Google Scholar]
  28. Lenczowski J. M., Dominguez L., Eder A. M., King L. B., Zacharchuk C. M., Ashwell J. D. Lack of a role for Jun kinase and AP-1 in Fas-induced apoptosis. Mol Cell Biol. 1997 Jan;17(1):170–181. doi: 10.1128/mcb.17.1.170. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Li P., Nijhawan D., Budihardjo I., Srinivasula S. M., Ahmad M., Alnemri E. S., Wang X. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell. 1997 Nov 14;91(4):479–489. doi: 10.1016/s0092-8674(00)80434-1. [DOI] [PubMed] [Google Scholar]
  30. Maruo T., Shibata K., Kimura A., Hoshina M., Mochizuki M. Tumor-associated antigen, TA-4, in the monitoring of the effects of therapy for squamous cell carcinoma of the uterine cervix. Serial determinations and tissue localization. Cancer. 1985 Jul 15;56(2):302–308. doi: 10.1002/1097-0142(19850715)56:2<302::aid-cncr2820560217>3.0.co;2-t. [DOI] [PubMed] [Google Scholar]
  31. Mino N., Iio A., Hamamoto K. Availability of tumor-antigen 4 as a marker of squamous cell carcinoma of the lung and other organs. Cancer. 1988 Aug 15;62(4):730–734. doi: 10.1002/1097-0142(19880815)62:4<730::aid-cncr2820620415>3.0.co;2-w. [DOI] [PubMed] [Google Scholar]
  32. Miyashita T., Krajewski S., Krajewska M., Wang H. G., Lin H. K., Liebermann D. A., Hoffman B., Reed J. C. Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene. 1994 Jun;9(6):1799–1805. [PubMed] [Google Scholar]
  33. Murakami A., Suminami Y., Sakaguchi Y., Nawata S., Numa F., Kishi F., Kato H. Specific detection and quantitation of SCC antigen 1 and SCC antigen 2 mRNAs by fluorescence-based asymmetric semi-nested reverse transcription PCR. Tumour Biol. 2000 Jul-Aug;21(4):224–234. doi: 10.1159/000030128. [DOI] [PubMed] [Google Scholar]
  34. Natoli G., Costanzo A., Ianni A., Templeton D. J., Woodgett J. R., Balsano C., Levrero M. Activation of SAPK/JNK by TNF receptor 1 through a noncytotoxic TRAF2-dependent pathway. Science. 1997 Jan 10;275(5297):200–203. doi: 10.1126/science.275.5297.200. [DOI] [PubMed] [Google Scholar]
  35. Nawata S., Nakamura K., Tanaka T., Numa F., Suminami Y., Tsunaga N., Kakegawa H., Katunuma N., Kato H. Electrophoretic analysis of the "cross-class" interaction between novel inhibitory serpin, squamous cell carcinoma antigen-1 and cysteine proteinases. Electrophoresis. 1997 May;18(5):784–789. doi: 10.1002/elps.1150180521. [DOI] [PubMed] [Google Scholar]
  36. Nawata S., Tsunaga N., Numa F., Tanaka T., Nakamura K., Kato H. Serine protease inhibitor activity of recombinant squamous cell carcinoma antigen towards chymotrypsin, as demonstrated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Electrophoresis. 1995 Jun;16(6):1027–1030. doi: 10.1002/elps.11501601173. [DOI] [PubMed] [Google Scholar]
  37. Nemoto S., Xiang J., Huang S., Lin A. Induction of apoptosis by SB202190 through inhibition of p38beta mitogen-activated protein kinase. J Biol Chem. 1998 Jun 26;273(26):16415–16420. doi: 10.1074/jbc.273.26.16415. [DOI] [PubMed] [Google Scholar]
  38. Nishina H., Fischer K. D., Radvanyi L., Shahinian A., Hakem R., Rubie E. A., Bernstein A., Mak T. W., Woodgett J. R., Penninger J. M. Stress-signalling kinase Sek1 protects thymocytes from apoptosis mediated by CD95 and CD3. Nature. 1997 Jan 23;385(6614):350–353. doi: 10.1038/385350a0. [DOI] [PubMed] [Google Scholar]
  39. Nozawa S., Kojima M., Tukazaki K., Sakayori M., Iizuka R., Kagiyama N. In vitro and in vivo induction of squamous cell carcinoma antigen (SCC) in a uterine cervical cancer cell line (SKG-IIIa) with peplomycin and sodium butyrate. Asia Oceania J Obstet Gynaecol. 1990 Jun;16(2):153–160. doi: 10.1111/j.1447-0756.1990.tb00018.x. [DOI] [PubMed] [Google Scholar]
  40. Numa F., Hirabayashi K., Tsunaga N., Kato H., O'Rourke K., Shao H., Stechmann-Lebakken C., Varani J., Rapraeger A., Dixit V. M. Elevated levels of syndecan-1 expression confer potent serum-dependent growth in human 293T cells. Cancer Res. 1995 Oct 15;55(20):4676–4680. [PubMed] [Google Scholar]
  41. Park D. S., Stefanis L., Yan C. Y., Farinelli S. E., Greene L. A. Ordering the cell death pathway. Differential effects of BCL2, an interleukin-1-converting enzyme family protease inhibitor, and other survival agents on JNK activation in serum/nerve growth factor-deprived PC12 cells. J Biol Chem. 1996 Sep 6;271(36):21898–21905. doi: 10.1074/jbc.271.36.21898. [DOI] [PubMed] [Google Scholar]
  42. Remold-O'Donnell E. The ovalbumin family of serpin proteins. FEBS Lett. 1993 Jan 4;315(2):105–108. doi: 10.1016/0014-5793(93)81143-n. [DOI] [PubMed] [Google Scholar]
  43. Roulston A., Reinhard C., Amiri P., Williams L. T. Early activation of c-Jun N-terminal kinase and p38 kinase regulate cell survival in response to tumor necrosis factor alpha. J Biol Chem. 1998 Apr 24;273(17):10232–10239. doi: 10.1074/jbc.273.17.10232. [DOI] [PubMed] [Google Scholar]
  44. Sakaguchi Y., Kishi F., Murakami A., Suminami Y., Kato H. Structural analysis of human SCC antigen 2 promoter. Biochim Biophys Acta. 1999 Jan 18;1444(1):111–116. doi: 10.1016/s0167-4781(98)00259-0. [DOI] [PubMed] [Google Scholar]
  45. Schick C., Kamachi Y., Bartuski A. J., Cataltepe S., Schechter N. M., Pemberton P. A., Silverman G. A. Squamous cell carcinoma antigen 2 is a novel serpin that inhibits the chymotrypsin-like proteinases cathepsin G and mast cell chymase. J Biol Chem. 1997 Jan 17;272(3):1849–1855. doi: 10.1074/jbc.272.3.1849. [DOI] [PubMed] [Google Scholar]
  46. Schick C., Pemberton P. A., Shi G. P., Kamachi Y., Cataltepe S., Bartuski A. J., Gornstein E. R., Brömme D., Chapman H. A., Silverman G. A. Cross-class inhibition of the cysteine proteinases cathepsins K, L, and S by the serpin squamous cell carcinoma antigen 1: a kinetic analysis. Biochemistry. 1998 Apr 14;37(15):5258–5266. doi: 10.1021/bi972521d. [DOI] [PubMed] [Google Scholar]
  47. Schneider S. S., Schick C., Fish K. E., Miller E., Pena J. C., Treter S. D., Hui S. M., Silverman G. A. A serine proteinase inhibitor locus at 18q21.3 contains a tandem duplication of the human squamous cell carcinoma antigen gene. Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3147–3151. doi: 10.1073/pnas.92.8.3147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Sluss H. K., Barrett T., Dérijard B., Davis R. J. Signal transduction by tumor necrosis factor mediated by JNK protein kinases. Mol Cell Biol. 1994 Dec;14(12):8376–8384. doi: 10.1128/mcb.14.12.8376. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Suminami Y., Kishi F., Sekiguchi K., Kato H. Squamous cell carcinoma antigen is a new member of the serine protease inhibitors. Biochem Biophys Res Commun. 1991 Nov 27;181(1):51–58. doi: 10.1016/s0006-291x(05)81380-4. [DOI] [PubMed] [Google Scholar]
  50. Suminami Y., Nagashima S., Vujanovic N. L., Hirabayashi K., Kato H., Whiteside T. L. Inhibition of apoptosis in human tumour cells by the tumour-associated serpin, SCC antigen-1. Br J Cancer. 2000 Feb;82(4):981–989. doi: 10.1054/bjoc.1999.1028. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Takekawa M., Saito H. A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK. Cell. 1998 Nov 13;95(4):521–530. doi: 10.1016/s0092-8674(00)81619-0. [DOI] [PubMed] [Google Scholar]
  52. Takeshima N., Nakamura K., Takeda O., Morioka H., Tamura H., Takasugi N., Kato H. Individualization of the cutoff value for serum squamous-cell carcinoma antigen using a sensitive enzyme immunoassay. Tumour Biol. 1990;11(3):167–172. doi: 10.1159/000217651. [DOI] [PubMed] [Google Scholar]
  53. Tewari M., Dixit V. M. Fas- and tumor necrosis factor-induced apoptosis is inhibited by the poxvirus crmA gene product. J Biol Chem. 1995 Feb 17;270(7):3255–3260. doi: 10.1074/jbc.270.7.3255. [DOI] [PubMed] [Google Scholar]
  54. Tewari M., Quan L. T., O'Rourke K., Desnoyers S., Zeng Z., Beidler D. R., Poirier G. G., Salvesen G. S., Dixit V. M. Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase. Cell. 1995 Jun 2;81(5):801–809. doi: 10.1016/0092-8674(95)90541-3. [DOI] [PubMed] [Google Scholar]
  55. Tewari M., Telford W. G., Miller R. A., Dixit V. M. CrmA, a poxvirus-encoded serpin, inhibits cytotoxic T-lymphocyte-mediated apoptosis. J Biol Chem. 1995 Sep 29;270(39):22705–22708. doi: 10.1074/jbc.270.39.22705. [DOI] [PubMed] [Google Scholar]
  56. Wagenknecht B., Schulz J. B., Gulbins E., Weller M. Crm-A, bcl-2 and NDGA inhibit CD95L-induced apoptosis of malignant glioma cells at the level of caspase 8 processing. Cell Death Differ. 1998 Oct;5(10):894–900. doi: 10.1038/sj.cdd.4400435. [DOI] [PubMed] [Google Scholar]
  57. Wyllie A. H., Kerr J. F., Currie A. R. Cell death: the significance of apoptosis. Int Rev Cytol. 1980;68:251–306. doi: 10.1016/s0074-7696(08)62312-8. [DOI] [PubMed] [Google Scholar]
  58. Xia Z., Dickens M., Raingeaud J., Davis R. J., Greenberg M. E. Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science. 1995 Nov 24;270(5240):1326–1331. doi: 10.1126/science.270.5240.1326. [DOI] [PubMed] [Google Scholar]
  59. Yamazaki T., Aoki Y. Cathepsin G enhances human natural killer cytotoxicity. Immunology. 1998 Jan;93(1):115–121. doi: 10.1046/j.1365-2567.1998.00397.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Yang X., Khosravi-Far R., Chang H. Y., Baltimore D. Daxx, a novel Fas-binding protein that activates JNK and apoptosis. Cell. 1997 Jun 27;89(7):1067–1076. doi: 10.1016/s0092-8674(00)80294-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Zhan Q., Fan S., Bae I., Guillouf C., Liebermann D. A., O'Connor P. M., Fornace A. J., Jr Induction of bax by genotoxic stress in human cells correlates with normal p53 status and apoptosis. Oncogene. 1994 Dec;9(12):3743–3751. [PubMed] [Google Scholar]
  62. Zhang J., Gao J. X., Salojin K., Shao Q., Grattan M., Meagher C., Laird D. W., Delovitch T. L. Regulation of fas ligand expression during activation-induced cell death in T cells by p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase. J Exp Med. 2000 Mar 20;191(6):1017–1030. doi: 10.1084/jem.191.6.1017. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES