Molecular & Cellular Toxicology

The Korean Society of Toxicogenomics and Toxicoproteomics (대한독성유전 단백체학회)
권호 표지

Detection of Serum Anti-Extracellular Protein Kinase a Autoantibodies as a Potential Tumor Marker

  • Lee, Seung-Ho (Department of Biochemistry & Molecular Biology, Korea University) ;
  • Kim, Ki-Nam (Department of Biochemistry & Molecular Biology, Korea University) ;
  • Seo, Sang-Hui (Department of Biochemistry & Molecular Biology, Korea University) ;
  • Sohn, Sung-Hwa (Department of Biochemistry & Molecular Biology, Korea University) ;
  • Kim, Yu-Ri (Department of Biochemistry & Molecular Biology, Korea University) ;
  • Kim, Hye-Won (Department of Biochemistry & Molecular Biology, Korea University) ;
  • Choi, Chul-Won (Department of Internal Medicine, College of Medicine, Korea University) ;
  • Kim, Jun-Suk (Department of Internal Medicine, College of Medicine, Korea University) ;
  • Kim, Meyoung-Kon (Department of Biochemistry & Molecular Biology, Korea University)
  • Published : 2006.03.31
Download PDF
⟨ Previous Next ⟩

Abstract

In previous studies, it has been discovered that cancer cells not only overexpress regulatory subunit I (Rl)/protein kinase type I (PKA-I) but also secrete outside the cell an extracellular form of PKA (ECPKA) and that the ECPKA secretion detected in patients' serum is obviously greater than that found in non-cancer patients or healthy subjects. We now found that ECPKA elicits the formation of serum autoantibodies that can serve as a cancer diagnostic and prognostic marker. To measure the presence of anti-ECPKA autoantibody in the human sera, basic methodology for ECPKA assay was established an enzyme-linked immunosorbent assay (ELISA). We obtained serum samples from 199 patients with different types of cancer, and also obtained 31 serum samples to compare with ECPKA concentrations from non-cancer patients and 119 normal volunteers. Compared with normal or non-cancer patient sera, we found that the frequency of anti-ECPKA autoantibody was significantly higher in cancer patients (88%) than in those without cancer (17%). Furthermore the presence of anti-ECPKA autoantibodies in the serum of cancer patients was highly correlated with the site of metastasis. The immunoassay developed for anti-ECPKA antibodies is highly sensitive and specific. Therefore, this discovery of an autoantibody-based cancer diagnostic may have serious clinical application and may become an important advance over current technology.

Keywords

References

  1. Yamamoto, A., Shimizu, E., Ogura, T. & Sone, S. Detection of auto-antibodies against L-myc oncogene products in sera from lung cancer patients. Int. J Cancer 69, 283-289 (1996) https://doi.org/10.1002/(SICI)1097-0215(19960822)69:4<283::AID-IJC8>3.0.CO;2-T
  2. Stockert, E. et al. A survey of the humoral immune response of cancer patients to a panel of human tumor antigens. J Exp. Med. 187, 1349-1354 (1998) https://doi.org/10.1084/jem.187.8.1349
  3. Gure, A.O. et al. Human lung cancer antigens recognized by autologous antibodies: definition of a novel cDNA derived from the tumor suppressor gene locus on chromosome 3p21.3. Cancer Res. 58, 1034-1041 (1998)
  4. Sahin, U. et al. Human neoplasms elicit multiple specific immune responses in the autologous host. Proc. Natl. Acad. Sci. USA 92, 11810-11813 (1995)
  5. Chen, Y.T., et al. Identification of multiple cancer/ testis antigens by allogeneic antibody screening of a melanoma cell line library. Proc. Natl. Acad. Sci. USA 95, 6919-6923 (1998)
  6. Brichory et al. An immune response manifested by the common occurrence of annexins I and II autoantibodies and high circulating levels of IL-6 in lung cancer. Proc. Natl. Acad. Sci. USA 98, 9824-9829 (2001)
  7. Minenkova, O. et al. Identification of tumor-associated antigens by screening phage-displayed human cDNA libraries with sera from tumor patients. Int. J Cancer 106, 534-544 (2003) https://doi.org/10.1002/ijc.11269
  8. Zhong, L. et al. Antibodies to HSP70 and HSP90 in serum in non-small cell lung cancer patients. Cancer Detect Prev. 27, 285-290 (2003) https://doi.org/10.1016/S0361-090X(03)00097-7
  9. Old, L.J. & Chen, Y.T. New paths in human cancer serology. J Exp. Med. 187, 1163-1167 (1998) https://doi.org/10.1084/jem.187.8.1163
  10. Mintz, P.J. et al. Fingerprinting the circulating repertoire of antibodies from cancer patients. Nat. Biotechnol. 21, 57-63 (2003) https://doi.org/10.1038/nbt774
  11. Crawford, L.V., Pim, D.C. & Bulbrook, R.D. Detection of antibodies against the cellular protein p53 in sera from patients with breast cancer. Int. J Cancer 30, 403-408 (1982) https://doi.org/10.1002/ijc.2910300404
  12. Soussi, T. p53 Antibodies in the sera of patients with various types of cancer: a review. Cancer Res. 60, 1777-1788 (2000)
  13. Lubin, R. et al. p53 antibodies in patients with various types of cancer: assay, identification, and characterization. Clin. Cancer Res. 1, 1463-1469 (1995)
  14. Tan, E.M. Autoantibodies as reporters identifying aberrant cellular mechanisms in tumorigenesis. J Clin. Invest. 108, 1411-1415 (2001) https://doi.org/10.1172/JCI14451
  15. Krebs, E.G. & Beavo, J.A. Phosphorylation-dephosphorylation of enzymes. Annu Rev. Biochem. 48, 923-959 (1979) https://doi.org/10.1146/annurev.bi.48.070179.004423
  16. Dumont, J.E., Jauniaux, J.C. & Roger, P.P. The cyclic AMP-mediated stimulation of cell proliferation. Trends Biochem. Sci. 14, 67-71 (1989) https://doi.org/10.1016/0968-0004(89)90046-7
  17. Gottesman, M.M. & Fleischmann, R.D. The role of cAMP in regulating tumour cell growth. Cancer Surv. 5, 291-308 (1986)
  18. Cho-Chung, Y.S. Role of cyclic AMP receptor proteins in growth, differentiation, and suppression of malignancy: new approaches to therapy. Cancer Res. 50, 7093-7100 (1990)
  19. Landmark, B.F. et al. Identification, characterization, and hormonal regulation of 3′, 5′-cyclic adenosine monophosphate-dependent protein kinases in rat Sertoli cells. Endocrinology 129, 2345-2354 (1991) https://doi.org/10.1210/endo-129-5-2345
  20. Levy, F.O. et al. Molecular cloning, complementary deoxyribonucleic acid structure and predicted fulllength amino acid sequence of the hormone-inducible regulatory subunit of 3′-5′-cyclic adenosine monophosphate- dependent protein kinase from human testis. Mol. Endocrinol. 2, 1364-1373 (1988) https://doi.org/10.1210/mend-2-12-1364
  21. McKnight, G.S. et al. Analysis of the cAMP-dependent protein kinase system using molecular genetic approaches. Recent Prog. Horm. Res. 44, 307-335 (1988)
  22. Beebe, S.J. The cAMP-dependent protein kinases and cAMP signal transduction. Semin. Cancer Biol. 5, 285-294 (1994)
  23. Weinstein, L.S., Yu, S., Warner, D.R. & Liu, J. Endocrine manifestations of stimulatory G protein alphasubunit mutations and the role of genomic imprinting. Endocr. Rev. 22, 675-705 (2001) https://doi.org/10.1210/er.22.5.675
  24. Stratakis, C.A., Kirschner, L.S. & Carney, J.A. Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation. J Clin. Endocrinol Metab. 86, 4041-4046 (2001) https://doi.org/10.1210/jc.86.9.4041
  25. Kirschner, L.S. et al. Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the carney complex. Hum. Mol. Genet. 9, 3037- 3046(2000) https://doi.org/10.1093/hmg/9.20.3037
  26. Kirschner et al. Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. Nat. Genet. 26, 89- 92 (2000) https://doi.org/10.1038/79238
  27. Cho-Chung, Y.S. Protein kinase A-directed antisense restrains cancer growth: sequence-specific inhibition of gene expression. Antisense Nucleic Acid Drug Dev. 6, 237-244 (1996) https://doi.org/10.1089/oli.1.1996.6.237
  28. Tan, E.M. Antinuclear antibodies: diagnostic markers for autoimmune diseases and probes for cell biology. Adv. Immunol. 44, 93-151 (1989) https://doi.org/10.1016/S0065-2776(08)60641-0
  29. Derk, C.T., Sakkas, L.I., Rasheed, M., Artlett, C. & Jimenez, S.A. Autoantibodies in patients with systemic sclerosis and cancer: a case-control study. J Rheumatol. 30, 1994-1996(2003)
  30. Hanahan, D. & Weinberg, R.A. The hallmarks of cancer. Cell 100, 57-70 (2000) https://doi.org/10.1016/S0092-8674(00)81683-9
  31. Notkins, A.L. & Lernmark, A. Autoimmune type 1 diabetes: resolved and unresolved issues. J Clin. Invest. 108, 1247-1252 (2001) https://doi.org/10.1172/JCI14257
  32. Hollstein, M., Sidransky, D., Vogelstein, B. & Harris, C.C. p53 mutations in human cancers. Science 253, 49-53 (1991) https://doi.org/10.1126/science.1905840
  33. Roth, J. et al. p53 as a target for cancer vaccines: recombinant canarypox virus vectors expressing p53 protect mice against lethal tumor cell challenge. Proc. Natl. Acad. Sci. USA 93, 4781-4786(1996 )
  34. Lee, S.Y. et al. Immunomic analysis of human sarcoma. Proc. Natl. Acad. Sci. USA 100, 2651-2656 (2003)