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Tumor Biology

, Volume 32, Issue 4, pp 671–676 | Cite as

Expression of FK506 binding protein 65 (FKBP65) is decreased in epithelial ovarian cancer cells compared to benign tumor cells and to ovarian epithelium

  • Rudi Henriksen
  • Flemming Brandt Sørensen
  • Torben Falck Ørntoft
  • Karin Birkenkamp-Demtroder
Research Article

Abstract

FK506 binding protein 65 (FKBP65) belongs to a group of proteins termed immunophilins that have a high binding affinity to immunosuppressant drugs as FK506 (tacrolimus) and rapamycin (sirolimus). Treatment of female premenopausal women with tacrolimus, which binds to FKBP65, has been reported to be followed by a strongly increased risk of ovarian cysts. We performed the present study to reveal how FKBP65 is expressed in the ovary and in ovarian tumors and to see if this expression might be related to ovarian tumor development, a relationship we have found in colorectal cancer. Biopsies from prospectively collected samples from ovaries and benign, borderline, and invasive ovarian tumors were analyzed for expression of FKBP65 by immunohistochemistry. The expression was compared to survival and several clinicopathological parameters. FKBP65 is strongly expressed in ovarian epithelium and in benign ovarian tumor cells. In the ovary, a positive staining was also found in endothelial cells of blood vessels. In non-invasive and in invasive malignant tumor cells, a decreased staining was observed, which was not correlated to stage, histology, or survival. A significant inversed correlation to expression of p53 was found. The differential expression of FKBP65 indicates a role in ovarian physiology as well as in ovarian tumor development. Our observations and the chromosomal localization of the FKBP65 gene indicate a tumor suppressor function of the FKBP65 protein in ovarian carcinogenesis.

Keywords

FK506 binding protein 65 Immunohistochemistry Ovary Ovarian cancer Rapamycin Tacrolimus 

Notes

Acknowledgments

We are grateful to Susanne Bruun and Pamela Celis for the excellent technical assistance. Professor Pirkko Härkönen, Department of Clinical Research Center, Lunds University, Malmoe, Sweden is deeply acknowledged for support with laboratory facilities and material.

Conflicts of interest

None

References

  1. 1.
    Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277–300.PubMedCrossRefGoogle Scholar
  2. 2.
    Ashworth A, Balkwill F, Bast RC, Berek JS, Kaye A, Boyd JA, et al. Opportunities and challenges in ovarian cancer research, a perspective from the 11th ovarian cancer action/HHMT forum, Lake Como, March 2007. Gynecol Oncol. 2008;108:652–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Wong AS, Leung PC. Role of endocrine and growth factors on the ovarian surface epithelium. J Obstet Gynaecol Res. 2007;33:3–16.PubMedCrossRefGoogle Scholar
  4. 4.
    Yoshida S, Furukawa N, Haruta S, Tanase Y, Kanayama S, Noguchi T, et al. Expression profiles of genes involved in poor prognosis of epithelial ovarian carcinoma: a review. Int J Gynecol Cancer. 2009;19:992–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Patterson CE, Gao J, Rooney AP, Davis EC. Genomic organization of mouse and human 65 kDa FK506-binding protein genes and evolution of the FKBP multigene family. Genomics. 2002;79:881–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Marcen R. Immunosuppressive drugs in kidney transplantation: impact on patient survival, and incidence of cardiovascular disease, malignancy and infection. Drugs. 2009;69:2227–43.PubMedCrossRefGoogle Scholar
  7. 7.
    Mukherjee S, Botha JF, Mukherjee U. Immunosuppression in liver transplantation. Curr Drug Targets. 2009;10:557–74.PubMedCrossRefGoogle Scholar
  8. 8.
    Fraile P, Garcia-Cosmes P, Martin P, Garcia-Bernalt V, Tabernero JM. Non-skin solid tumors as a cause of morbidity and mortality after liver transplantation. Transplant Proc. 2009;41:2433–4.PubMedCrossRefGoogle Scholar
  9. 9.
    Olesen SH, Christensen LL, Sorensen FB, Cabezon T, Laurberg S, Orntoft TF, et al. Human FK506 binding protein 65 is associated with colorectal cancer. Mol Cell Proteomics. 2005;4:534–44.PubMedCrossRefGoogle Scholar
  10. 10.
    Alfadhli E, Koh A, Albaker W, Bhargava R, Ackerman T, McDonald C, et al. High prevalence of ovarian cysts in premenopausal women receiving sirolimus and tacrolimus after clinical islet transplantation. Transpl Int. 2009;22:622–5.PubMedCrossRefGoogle Scholar
  11. 11.
    Henriksen R, Funa K, Wilander E, Backstrom T, Ridderheim M, Oberg K. Expression and prognostic significance of platelet-derived growth factor and its receptors in epithelial ovarian neoplasms. Cancer Res. 1993;53:4550–4.PubMedGoogle Scholar
  12. 12.
    Henriksen R, Gobl A, Wilander E, Oberg K, Miyazono K, Funa K. Expression and prognostic significance of TGF-beta isotypes, latent TGF-beta 1 binding protein, TGF-beta type I and type II receptors, and endoglin in normal ovary and ovarian neoplasms. Lab Invest. 1995;73:213–20.PubMedGoogle Scholar
  13. 13.
    Henriksen R, Strang P, Wilander E, Backstrom T, Tribukait B, Oberg K. p53 expression in epithelial ovarian neoplasms: relationship to clinical and pathological parameters, Ki-67 expression and flow cytometry. Gynecol Oncol. 1994;53:301–6.PubMedCrossRefGoogle Scholar
  14. 14.
    Armitage BG. Statistical methods in medical research. 2nd ed. Oxford: Blackwell; 1987.Google Scholar
  15. 15.
    Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Amer Statist Assn. 1958;53:457–81.CrossRefGoogle Scholar
  16. 16.
    Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep. 1966;50:163–70.PubMedGoogle Scholar
  17. 17.
    Barik S. Immunophilins: for the love of proteins. Cell Mol Life Sci. 2006;63:2889–900.PubMedCrossRefGoogle Scholar
  18. 18.
    Kang CB, Hong Y, Dhe-Paganon S, Yoon HS. FKBP family proteins: immunophilins with versatile biological functions. Neurosignals. 2008;16:318–25.PubMedCrossRefGoogle Scholar
  19. 19.
    Patterson CE, Abrams WR, Wolter NE, Rosenbloom J, Davis EC. Developmental regulation and coordinate reexpression of FKBP65 with extracellular matrix proteins after lung injury suggest a specialized function for this endoplasmic reticulum immunophilin. Cell Stress Chaperones. 2005;10:285–95.PubMedCrossRefGoogle Scholar
  20. 20.
    Ishikawa Y, Vranka J, Wirz J, Nagata K, Bachinger HP. The rough endoplasmic reticulum-resident FK506-binding protein FKBP65 is a molecular chaperone that interacts with collagens. J Biol Chem. 2008;283:31584–90.PubMedCrossRefGoogle Scholar
  21. 21.
    Shah R, Smith P, Purdie C, Quinlan P, Baker L, Aman P, et al. The prolyl 3-hydroxylases P3H2 and P3H3 are novel targets for epigenetic silencing in breast cancer. Br J Cancer. 2009;100:1687–96.PubMedCrossRefGoogle Scholar
  22. 22.
    Xue J, Li X, Jiao S, Wei Y, Wu G, Fang J. Prolyl hydroxylase-3 is down-regulated in colorectal cancer cells and inhibits IKKbeta independent of hydroxylase activity. Gastroenterology. 2010;138:606–15.PubMedCrossRefGoogle Scholar
  23. 23.
    Alanay Y, Avaygan H, Camacho N, Utine GE, Boduroglu K, Aktas D, et al. Mutations in the gene encoding the RER protein FKBP65 cause autosomal-recessive osteogenesis imperfecta. Am J Hum Genet. 2010;86:551–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Godwin AK, Vanderveer L, Schultz DC, Lynch HT, Altomare DA, Buetow KH, et al. A common region of deletion on chromosome 17q in both sporadic and familial epithelial ovarian tumors distal to BRCA1. Am J Hum Genet. 1994;55:666–77.PubMedGoogle Scholar
  25. 25.
    Kirken RA, Wang YL. Molecular actions of sirolimus: sirolimus and mTor. Transplant Proc. 2003;35:227S–30S.PubMedCrossRefGoogle Scholar
  26. 26.
    Seufferlein T, Rozengurt E. Rapamycin inhibits constitutive p70s6k phosphorylation, cell proliferation, and colony formation in small cell lung cancer cells. Cancer Res. 1996;56:3895–7.PubMedGoogle Scholar
  27. 27.
    Giordano A, Romano S, Mallardo M, D’Angelillo A, Cali G, Corcione N, et al. FK506 can activate transforming growth factor-beta signalling in vascular smooth muscle cells and promote proliferation. Cardiovasc Res. 2008;79:519–26.PubMedCrossRefGoogle Scholar
  28. 28.
    Romano S, Di PA, Sorrentino A, Bisogni R, Sivero L, Romano MF. FK506 binding proteins as targets in anticancer therapy. Anticancer Agents Med Chem. 2010;10:651–6.PubMedGoogle Scholar
  29. 29.
    Donato ML, Levenback C, Gershenson DM, McMeekin S, Champlin RE. Matched unrelated donor bone marrow transplantation for the treatment of platinum refractory ovarian carcinoma: a case report. Gynecol Oncol. 2004;92:365–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Stippel DL, Kasper HU, Schleimer K, Tox U, Bangard C, Holscher AH, et al. Successful use of sirolimus in a patient with bulky ovarian metastasis of hepatocellular carcinoma after liver transplantation. Transplant Proc. 2005;37:2185–7.PubMedCrossRefGoogle Scholar
  31. 31.
    Chinnakotla S, Davis GL, Vasani S, Kim P, Tomiyama K, Sanchez E, et al. Impact of sirolimus on the recurrence of hepatocellular carcinoma after liver transplantation. Liver transplant. 2009;15:1834–42.CrossRefGoogle Scholar
  32. 32.
    Andersson Y, Engebraaten O, Fodstad O. Synergistic anti-cancer effects of immunotoxin and cyclosporin in vitro and in vivo. Br J Cancer. 2009;101:1307–15.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2011

Authors and Affiliations

  • Rudi Henriksen
    • 1
  • Flemming Brandt Sørensen
    • 2
  • Torben Falck Ørntoft
    • 3
  • Karin Birkenkamp-Demtroder
    • 3
  1. 1.Department of Obstetrics and Gynecology, University Hospital SUSLunds UniversityMalmoeSweden
  2. 2.Department of Clinical PathologyVejle HospitalVejleDenmark
  3. 3.Department of Molecular Medicine (MOMA), Center for Clinical Cancer Research (CMCC)Aarhus University Hospital, SkejbyAarhus NDenmark

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