Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
권호 표지
DOI QR코드

DOI QR Code

Roles of Prostatic Acid Phosphatase in Prostate Cancer

Prostatic acid phosphatase의 전립선 암에서의 역할

  • Kong, Hoon-Young (Department of Molecular Biology, Institute of Nanosensor and Biotechnology, Dankook University) ;
  • Lee, Hak-Jong (Department of Radiology, Seoul National University College of Medicine and Seoul National University Bundang Hospital) ;
  • Byun, Jong-Hoe (Department of Molecular Biology, Institute of Nanosensor and Biotechnology, Dankook University)
  • 공훈영 (단국대학교 분자생물학과, 나노센서바이오텍연구소) ;
  • 이학종 (서울대학교 의과대학, 분당서울대학교병원 영상의학과) ;
  • 변종회 (단국대학교 분자생물학과, 나노센서바이오텍연구소)
  • Received : 2011.05.24
  • Accepted : 2011.06.04
  • Published : 2011.06.30
Download PDF
⟨ Previous Next ⟩

Abstract

Prostatic acid phosphatase (PAP) is one of the widely used biomarkers in the diagnosis of prostate cancer. It was initially identified in 1935 and is the most abundant phosphatase in the human prostate. PAP is a prostate-specific enzyme that is synthesized in prostate epithelial cells. It belongs to the acid phosphatase group that shows enzymatic activity in acidic conditions. PAP is abundant in prostatic fluid and is thought to have a role in fertilization and oligospermia. It also has a potential role in reducing chronic pain. But one of the most apparent functions of PAP is the dephosphorylation of macromolecules such as HER-2 and PI3P that are involved in the ERK1/2 and MAPK pathways, which in turn leads to inhibition of cell growth and tumorigenesis. Currently, clinical trials using PAP DNA vaccine are underway and FDA-approved immunotherapy using PAP is commercially available. Despite these clinically important aspects, molecular mechanisms underlying PAP regulation are not fully understood. The promoter region of PAP was reported to be regulated by NF-${\kappa}B$, TNF-${\alpha}$, IL-1, androgen and androgen receptors. Here, the features of PAP gene and protein structures together with the function, regulation and roles of PAP in prostate cancer are discussed.

Prostatic acid phosphatase (PAP)는 전립선 암의 진단에 널리 사용되는 표지자로서 1935년 처음으로 동정되었고 인체 전립선에 가장 많이 존재하는 탈 인산화효소이다. PAP는 prostate epithelial cells에서 합성되는 전립선 특이적인 효소로서, 산성 환경에서 효소활성을 띠는 acid phosphatase 그룹에 속한다. PAP는 전립선액에 풍부히 존재하여 수정, 정자부족증, 만성통증의 감소에 관여한다. 그러나 가장 눈에 띄는 기능은 ERK1/2와 MAPK 경로에 관계된 HER-2와 PI3P의 탈 인산화를 유도하여 세포 성장 신호를 억제하고 전립선 암의 억제자로 작용하는 것이다. 최근 PAP DNA 백신을 이용하는 임상시험이 현재 진행 중이고, PAP를 이용한 immunotherapy를 통해 전립선 암을 치료하는 방법이 FDA의 승인을 받아 시행되고 있다. 이러한 PAP의 임상적 중요성에도 불구하고 현재까지 PAP의 분자적 조절기작에 대한 이해는 제한적이라 PAP에 대한 많은 연구가 필요한 실정이다. PAP는 NF-${\kappa}B$, TNF-${\alpha}$, IL-1 및 androgen과 androgen receptor에 의하여 promoter region이 조절된다고 알려졌다. 본 총설에서는 현재까지 밝혀진 PAP 유전자 및 단백질의 특징들과 더불어 전립선 암에서의 PAP의 기능, 발현 조절, 역할들을 종합하였다.

Keywords

References

  1. Afzal, S., M. Ahmad, S. Mushtaq, A. Mubarik, A. H. Qureshi, and S. A. Khan. 2003. Morphological features correlation with serum tumour markers in prostatic carcinoma. J. Coll. Physicians Surg. Pak. 13, 511-514.
  2. Azumi, N., S. T. Traweek, and H. Battifora. 1991. Prostatic acid phosphatase in carcinoid tumors. Immunohistochemical and immunoblot studies. Am. J. Surg. Pathol. 15, 785-790. https://doi.org/10.1097/00000478-199108000-00009
  3. Bais, R., A. Huxtable, and J. B. Edwards. 1983. Human prostatic acid phosphatase: properties of the native enzyme, and the enzyme-antibody complex. Annu. Clin. Biochem. 20, 374-380 https://doi.org/10.1177/000456328302000609
  4. Banas, B., D. Blaschke, F. Fittler, and W. Hörz. 1994. Analysis of the promoter of the human prostatic acid phosphatase gene. Biochim. Biophys. Acta 1217, 188-194. https://doi.org/10.1016/0167-4781(94)90033-7
  5. Boissonneault, M., A. Chapdelaine, and S. Chevalier. 1995. The enhancement by pervanadate of tyrosine phosphorylation on prostatic proteins occurs through the inhibition of membrane-associated tyrosine phosphatases. Mol. Cell Biochem. 153, 139-144. https://doi.org/10.1007/BF01075929
  6. Carballido, E. and M. Fishman. 2011. Sipuleucel-T: Prototype for development of anti-tumor vaccines. Curr. Oncol. Rep. 13, 112-119. https://doi.org/10.1007/s11912-011-0152-5
  7. Cheever, M. A. and C. Higano. 2011. PROVENGE (Sipuleucel-T) in Prostate Cancer: The First FDA Approved Therapeutic Cancer Vaccine. Clin. Cancer Res. [Epub ahead of print]
  8. Dave, B. N. and T. T. Rindani. 1988. Acid phosphatase activity in human semen. Int. J. Fertil. 33, 45-47.
  9. Fang, L. C., M. Dattoli, A. Taira, L. True, R. Sorace, and K. Wallner. Prostatic acid phosphatase adversely affects cause-specific survival in patients with intermediate to high-risk prostate cancer treated with brachytherapy. Urology 71, 146-150.
  10. Gieselmann, V., P. Lemansky, A. Hasilik, K. von Figura, A. Waheed, and R. L. van Etten. 1986. Human tartrate-inhibitable lysosomal acid phosphatase. Purification, characterization, biosynthesis and intracellular transport. Acta Biochim. Pol. 33, 119-126.
  11. Goldfarb, D. A., B. S. Stein, M. Shamszadeh, and R. O. Petersen. 1986. Age-related changes in tissue levels of prostatic acid phosphatase and prostate specific antigen. J. Urol. 136, 1266-1269.
  12. Graddis, T. J., C. J. McMahan, J. Tamman, K. J. Page, and J. B. Trager. 2011. Prostatic acid phosphatase expression in human tissues. Int. J. Clin. Exp. Pathol. 4, 295-306.
  13. Gunia, S., S. Koch, M. May, M. Dietel, and A. Erbersdobler. 2009. Expression of prostatic acid phosphatase (PSAP) in transurethral resection specimens of the prostate is predictive of histopathologic tumor stage in subsequent radical prostatectomies. Virchows. Arch. 454, 573-579. https://doi.org/10.1007/s00428-009-0759-1
  14. Hakalahti, L., P. Vihko, P. Henttu, H. Autio-Harmainen, Y. Soini, and R. Vihko. 1993. Evaluation of PAP and PSA gene expression in prostatic hyperplasia and prostatic carcinoma using northern-blot analyses, in situ hybridization and immunohistochemical stainings with monoclonal and bispecific antibodies. Int. J. Cancer 55, 590-597. https://doi.org/10.1002/ijc.2910550413
  15. Jakob, C. G., K. Lewinski, R. Kuciel, W. Ostrowski, and L. Lebioda. 2000. Crystal structure of human prostatic acid phosphatase. Prostate 42, 211-218. https://doi.org/10.1002/(SICI)1097-0045(20000215)42:3<211::AID-PROS7>3.0.CO;2-U
  16. Kuciel, R., A. Bakalova, A. Mazurkiewicz, A. Bilska, and W. Ostrowski. 1990. Is the subunit of prostatic phosphatase active? Reversible denaturation of prostatic acid phosphatase. Biochem. Int. 22, 329-334. https://doi.org/10.1016/0020-711X(90)90134-O
  17. Kutcher, W., and H. Wolbergs. 1935. Prostataphosphatase. Z. Physiol. Chem. 236, 237-240. https://doi.org/10.1515/bchm2.1935.236.4-6.237
  18. Lee, H. C., R. E. Gaensslen, E. M. Pagliaro, and B. Novitch. 1988. Two-dimensional absorption-inhibition. J. Forensic Sci. 33, 1127-1138.
  19. Lin, M. F. and G. M. Clinton. 1986. Human prostatic acid phosphatase has phosphotyrosyl protein phosphatase activity. Biochem. J. 235, 351-357.
  20. Lin, M. F., M. S. Lee, X. W. Zhou, J. C. Andressen, T. C. Meng, S. L. Johansson, W. W. West, R. J. Taylor, J. R. Anderson, and F. F. Lin. 2001. Decreased expression of cellular prostatic acid phosphatase increases tumorigenicity of human prostate cancer cells. J. Urol. 166, 1943-1950. https://doi.org/10.1016/S0022-5347(05)65725-4
  21. Lin, M. F., R. Garcia-Arenas, X. Z. Xia, B. Biela, and F. F. Lin. 1994. The cellular level of prostatic acid phosphatase and the growth of human prostate carcinoma cells. Differentiation 57, 143-149. https://doi.org/10.1046/j.1432-0436.1994.5720143.x
  22. Meng, T. C., M. S. Lee, and M. F. Lin. 2000. Interaction between protein tyrosine phosphatase and protein tyrosine kinase is involved in androgen-promoted growth of human prostate cancer cells. Oncogene 19, 2664-2677. https://doi.org/10.1038/sj.onc.1203576
  23. Merrick, G. S., W. M. Butler, K. E. Wallner, A. Allen, J. L. DeFilippo, and E. Adamovich. 2005. Enzymatic prostatic acid phosphatase in the clinical staging of patients diagnosed with prostate cancer. W. V. Med. J. 101, 116-119.
  24. Okar, D. A., D. H. Live, M. H. Devany, and A. J. Lange. 2000. Mechanism of the bisphosphatase reaction of 6-phosphofructo- 2-kinase/fructose-2,6-bisphosphatase probed by (1)H-(15)N NMR spectroscopy. Biochemistry 39, 9754-9762. https://doi.org/10.1021/bi000815k
  25. Olson, B. M., T. P. Frye, L. E. Johnson, L. Fong, K. L. Knutson, M. L. Disis, and D. G. McNeel. 2010. HLA-A2-restricted T-cell epitopes specific for prostatic acid phosphatase. Cancer Immunol. Immunother. 59, 943-53. https://doi.org/10.1007/s00262-010-0820-6
  26. Ostanin, K., A. Saeed, and R. L. Van Etten. 1994. Heterologous expression of human prostatic acid phosphatase and site-directed mutagenesis of the enzyme active site. J. Biol. Chem. 269, 8971-8978.
  27. Patrikainen, L., J. Shan, K. Porvari, and P. Vihko. 1999. Identification of the deoxyribonucleic acid-binding site of a regulatory protein involved in prostate-specific and androgen receptor-dependent gene expression. Endocrinology 140, 2063-2070. https://doi.org/10.1210/en.140.5.2063
  28. Pope, S. N. and I. R. Lee. 2005. Yeast two-hybrid identification of prostatic proteins interacting with human sex hormone-binding globulin. J. Steroid Biochem. Mol. Biol. 94, 203-208. https://doi.org/10.1016/j.jsbmb.2005.01.007
  29. Porvari, K., R. Kurkela, A. Kivinen, and P. Vihko. 1995. Differential androgen regulation of rat prostatic acid phosphatase transcripts. Biochem. Biophys. Res. Commun. 213, 861-868. https://doi.org/10.1006/bbrc.1995.2208
  30. Quintero, I. B., C. L. Araujo, A. E. Pulkka, R. S. Wirkkala, A. M. Herrala, E. L. Eskelinen, E. Jokitalo, P. A. Hellström, H. J. Tuominen, P. P. Hirvikoski, and P. T. Vihko. 2007. Prostatic acid phosphatase is not a prostate specific target. Cancer Res. 67, 6549-6554. https://doi.org/10.1158/0008-5472.CAN-07-1651
  31. Saini, M. S. and R. L. Van Etten. 1981. A clinical assay for prostatic acid phosphatase using choline phosphate as a substrate: comparison with thymolphthalein phosphate. Prostate 2, 359-368. https://doi.org/10.1002/pros.2990020404
  32. Saito, T., N. Hara, Y. Kitamura, and S. Komatsubara. 2007. Prostate-specific antigen/prostatic acid phosphatase ratio is significant prognostic factor in patients with stage IV prostate cancer. Urology 70, 702-705. https://doi.org/10.1016/j.urology.2007.05.019
  33. Shan, J. D., K Porvari, M. Ruokonen, A. Karhu, V. Launonen, P. Hedberg, J. Oikarinen, and P. Vihko. 1997. Steroid-involved transcriptional regulation of human genes encoding prostatic acid phosphatase, prostate-specific antigen, and prostate-specific glandular kallikrein. Endocrinology 138, 3764-3770. https://doi.org/10.1210/en.138.9.3764
  34. Shan, J., K. Porvari, A. Kivinen, L. Patrikainen, M. Halmekytö, J. Jänne, and P. Vihko. 2003. Tissue-specific expression of the prostatic acid phosphatase promoter constructs. Biochem. Biophys. Res. Commun. 311, 864-869. https://doi.org/10.1016/j.bbrc.2003.10.071
  35. Shan, J., K. Porvari, and P. Vihko. 2005. GAAAATATGATA-like elements in androgen-associated regulation of the prostatic acid phosphatase gene. J. Steroid Biochem. Mol. Biol. 96, 245-249. https://doi.org/10.1016/j.jsbmb.2005.04.031
  36. Sharma, S., A. Rauk, and A. H. Juffer. 2008. A DFT study on the formation of a phosphohistidine intermediate in prostatic acid phosphatase. J. Am. Chem. Soc. 130, 9708-9716. https://doi.org/10.1021/ja710047a
  37. Singh, G., P. G. Adaikan, and Y. K. Ng. 1996. Is senimal prostatic acid phosphatase a reliable marker for male infertility? Singapore Med. J. 37, 598-599.
  38. Sinha, A. A., D. E. Gleason, M. J. Wilson, M. R. Wick, P. K. Reddy, and C. E. Blackard. 1998. Relationship of prostatic acid phosphatase localization in human prostate by a monoclonal antibody with the Gleason grading system. Prostate 13, 1-15
  39. Skinningsrud, A. 1983. Acid phosphatases of the human placenta, characterization and immunological comparison with prostatic acid phosphatase. Enzyme 29, 250-259.
  40. Solin, T., M. Kontturi, R. Pohlmann, and P. Vihko. 1990. Gene expression and prostate specificity of human prostatic acid phosphatase (PAP): evaluation by RNA blot analyses. Biochim. Biophys. Acta 1048, 72-77. https://doi.org/10.1016/0167-4781(90)90024-V
  41. Van Etten, R. L., R. Davidson, P. E. Stevis, H. MacArthur, and D. L. Moore. 1991. Covalent structure, disulfide bonding, and identification of reactive surface and active site residues of human prostatic acid phosphatase. J. Biol. Chem. 266, 2313-2319.
  42. Veeramani, S., T. C. Yuan, S. J. Chen, F. F. Lin, J. E. Petersen, S. Shaheduzzaman, S. Srivastava, R. G. MacDonald, and M. F. Lin. 2005. Cellular prostatic acid phosphatase: a protein tyrosine phosphatase involved in androgen-independent proliferation of prostate cancer. Endocr. Relat. Cancer 12, 805-822. https://doi.org/10.1677/erc.1.00950
  43. Vihko, P. 1978. Characterization of the principal human prostatic acid phosphatase isoenzyme, purified by affinity chromatography and isoelectric focusing. Part II. Clin. Chem. 244, 1783-1787.
  44. Vihko, P., E. Sajanti, O. Jänne, L. Peltonen, and R. Vihko. 1978 Serum prostate-specific acid phosphatase: development and validation of a specific radioimmunoassay. Clin. Chem. 24, 1915-1919.
  45. Vihko, P., I. Quintero, A. E. Ronka, A. Herrala, P. Jantti, K. Porvari, Y. Lindqvist, H. Kaija, A. Pulkka, and J. Vuoristo. 2005. Acid phosphatase (PAcP) is PI(3)P-phosphatase and its inactivation leads to change of the cell polarity and invasive prostate cancer. Proceedings of the AACR, 96th Annual Meeting. Anaheim, CA, USA. Abstract 5239.
  46. Wang, Y., M. Harada, H. Yano, S. Ogasawara, H. Takedatsu, Y. Arima, S. Matsueda, A. Yamada, and K. Itoh. 2005. Prostatic acid phosphatase as a target molecule in specific immunotherapy for patients with nonprostate adenocarcinoma. J. Immunother. 28, 535-541. https://doi.org/10.1097/01.cji.0000175490.26937.22
  47. Winqvist, R., P. Virkkunen, K. H. Grzeschik, and P. Vihko. 1989. Chromosomal localization to 3q21---qter and two TaqI RFLPs of the human prostate-specific acid phosphatase gene (ACPP). Cytogenet. Cell Genet. 52, 68-71. https://doi.org/10.1159/000132842
  48. Zelivianski, S., D. Comeau, and M. F. Lin. 1998. Cloning and analysis of the promoter activity of the human prostatic acid phosphatase gene. Biochem. Biophys. Res. Commun. 245, 108-112. https://doi.org/10.1006/bbrc.1998.8386
  49. Zelivianski, S., R. Glowacki, and M. F. Lin. 2004. Transcriptional activation of the human prostatic acid phosphatase gene by NF-kappaB via a novel hexanucleotide- binding site. Nucleic Acids. Res. 32, 3566-3580. https://doi.org/10.1093/nar/gkh677
  50. Zelivianski, S., T. Igawa, S. Lim, R. Taylor, and M. F. Lin. 2002. Identification and characterization of regulatory elements of the human prostatic acid phosphatase promoter. Oncogene 21, 3696-3705. https://doi.org/10.1038/sj.onc.1205471
  51. Zhang, X. Q., M. S. Lee., S. Zelivianski, and M. F. Lin. 2001. Characterization of a prostate-specific tyrosine phosphatase by mutagenesis and expression in human prostate cancer cells. J. Biol. Chem. 276, 2544-2550. https://doi.org/10.1074/jbc.M006661200
  52. Zimmermann, H. 2009. Prostatic acid phosphatase, a neglected ectonucleotidase. Purinergic. Signal 5, 273-275. https://doi.org/10.1007/s11302-009-9157-z
  53. Zylka, M. J., N. A. Sowa, B. Taylor-Blake, M. A. Twomey, A. Herrala, V. Voikar, and P. Vihko. 2008. Prostatic acid phosphatase is an ectonucleotidase and suppresses pain by generating adenosine. Neuron 60, 111-122. https://doi.org/10.1016/j.neuron.2008.08.024

Cited by

  1. Emerging Roles of Human Prostatic Acid Phosphatase vol.21, pp.1, 2013, https://doi.org/10.4062/biomolther.2012.095