Increased expression of the RIα subunit of the cAMP-dependent protein kinase A is associated with advanced stage ovarian cancer

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Summary

The primary element in the cAMP signal transduction pathway is the cAMP-dependent protein kinase (PKA). Expression of the RIα subunit of type I PKA is elevated in a variety of human tumours and cancer cell lines. The purpose of this study was to assess the prognostic importance of RIα expression in patients with ovarian cancer. We have evaluated the expression of RIα in a panel of human ovarian tumours (n= 40) and five human ovarian cancer cell lines using quantitative reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis. The human ovarian cell lines OAW42 and OTN14 express high endogenous levels of RIα mRNA and protein (at significantly higher mRNA levels than high tissue expressors, P< 0.05). The ovarian cell line A2780 expresses low endogenous levels of RIα mRNA and protein (also at higher mRNA levels than low tissue expressors, P< 0.05). Quantitative RT-PCR revealed no significant difference in RIα mRNA expression between different ovarian histological subtypes in this study. No associations were found between RIα mRNA expression and differentiation state. RIα mRNA expression was significantly associated with tumour stage (P= 0.0036), and this remained significant in univariate analysis (P= 0.0002). A trend emerged between RIα mRNA expression levels and overall survival in univariate analysis (P= 0.051), however, by multivariate analysis, stage remained the major determinant of overall survival (P= 0.0001). This study indicates that in ovarian epithelial tumours high RIα mRNA expression is associated with advanced stage disease. RIα expression may be of predictive value in ovarian cancer and may be associated with dysfunctional signalling pathways in this cancer type.

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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

  1. Beebe, S. J. (1994). The cAMP-dependent protein kinases and cAMP signal transduction. Semin Cancer Biol 5: 285–294.

  2. Bradford, M. M. (1976). A rapid and sensitive method for the quantification of microgram quantities of protein utilising the principle of protein-dye binding. Anal Biochem 72: 248–254.

  3. Cho-Chung, Y. S. (1990). Role of cAMP receptor proteins in growth, differentiation, and suppression of malignancy: new approaches to therapy. Cancer Res 50: 7093–7100.

  4. Cho-Chung, Y. S. (1993). Differentiation therapy of cancer targeting the RIα regulatory subunit of cAMP-dependent protein kinase. Int J Oncol 3: 141–148.

  5. Land, J. A. (1987). Ovulation, ovulation induction and ovarian carcinoma. Baillières Clin Obstet Gynaecol 43: 455–470.

  6. Langdon, S. P., Lawrie, S. S. & Hay, F. G. (1988). Characterisation and properties of nine human ovarian adenocarcinoma cell lines. Cancer Res 48: 6166–6172.

  7. Leonard, M. W., Lim, K-C & Engel, J. D. (1993). Expression of the chicken GATA factor family during early erythoid development and differentiation. Development 119: 519–531.

  8. McDaid, H., Cairns, M. T., Church, S., White, P. & Johnston, P. G. (1997). Response to 8-Cl-cAMP in a panel of human cancer cell lines is dependent on intrinsic RIα expression levels. Proc Am Assoc Cancer Res 38: abstract 2823

  9. Miller, W. R., Hulme, M. J., McCallum, J., Cameron, D. A., Dixon, J. M. & Bartlett, J. M. S. (1996). Tumour RIα mRNA and response to tamoxifen in patients with breast cancer. Proc Am Assoc Cancer Res 37: abstact 1627

  10. Nesterova, M. & Cho-Chung, Y. S. (1995). A single-injection protein kinase A-directed antisense treatment to inhibit tumour growth. Nature Med 1: 528–533.

  11. NIH Consensus Statement (1994). Ovarian cancer: screening, treatment and follow-up. In NIH Consens Statment 12: 1–30.

  12. Parker, S. L., Tong, T., Bolden, S. & Wingo, P. A. (1996). Cancer statistics, 1996. CA Cancer Clin 46: 5–27.

  13. Reimann, K. V., Walsh, D. A. & Krebs, E. G. (1971). Purification and properties of rabbit skeletal muscle adenosine 3′,5′-monophosphate-dependent protein kinases. J Biol Chem 246: 1986

  14. Simpson, B. J. B., Ramage, A. D., Hulme, M. J., Burns, D. J., Katsaros, D., Langdon, S. P. & Miller, W. R. (1996). Cyclic adenosine 3′,5′-monophosphate-binding proteins in human ovarian cancer: correlations with clinicopathological features. Clin Cancer Res 2: 201–206.

  15. Tortora, G., Ciardiello, F., Pepe, S., Tagliaferri, P., Ruggiero, A., Bianco, C., Guarrasi, R., Miki, K. & Raffaele Bianco, A. (1995). Phase I clinical study with 8-Cl-cAMP and evaluation of immunological effects in cancer patients. Clin Cancer Res 51: 1600–1605.

  16. Van Niekerk, C. C., Poels, L. G., Jap, P. H., Smeets, D. F., Thomas, C. M., Ramaekers, F. C. & Voous, G. P. (1988). Characterisation of a human ovarian carcinoma cell line, OTN14 derived from a mucinous cystadenocarcinoma. Int J Cancer 42: 104–111.

  17. Walsh, D. A., Perkins, J. P. & Krebs, E. G. (1968). An adenosine 3′,5′-monophosphate-dependent protein kinase from rabbit skeletal muscle. J Biol Chem 243: 3763–3765.

  18. Whelan, S. L. & Ferlay, J. (1992). Cancer incidence in five continents. Age-specific and standardized incidence rates. IARC Sci Publ 120: 178–861.

  19. Wilson, A. P. (1984). Characterisation of a cell line derived from the ascites of a patient with papillary serous cystadenoma of the ovary. J Natl Cancer Inst 72: 513–521.

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McDaid, H., Cairns, M., Atkinson, R. et al. Increased expression of the RIα subunit of the cAMP-dependent protein kinase A is associated with advanced stage ovarian cancer. Br J Cancer 79, 933–939 (1999) doi:10.1038/sj.bjc.6690149

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Keywords

  • type I-cAMP-dependent protein kinase
  • reverse transcription polymerase chain reaction
  • ovarian cancer
  • cAMP

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