Role of Prostate Specific Antigen (PSA) in Pathogenesis of Prostate Cancer


Prostate cancer (PCa) is most common diagnosed cancer in men and it is second most common cause of male cancer death. Many factors have been implicated in the pathogenesis of PCa. Although many papers have discussed the prostate specific antigen (PSA) as biomarker of PCa, very few have addressed its rule in the carcinogenesis, metastasis and invasion of PCa. In this article we will review the pathological role of PSA, as a potential target in the therapeutics of PCa.

Share and Cite:

S. Altuwaijri, "Role of Prostate Specific Antigen (PSA) in Pathogenesis of Prostate Cancer," Journal of Cancer Therapy, Vol. 3 No. 4, 2012, pp. 331-336. doi: 10.4236/jct.2012.34043.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] A. Jemal, R. Siegel, E. Ward, Y. Hao, J. Xu and M. J. Thun, “Cancer Statistics,” CA: A Cancer Journal for Clinicians, Vol. 59, No. 4, 2009, pp. 225-249.doi:10.3322/caac.20006
[2] H. Gr?nberg, “Prostate Cancer Epidemiology,” Lancet, Vol. 361, No. 9360, 2003, pp. 859-864.doi:10.1016/S0140-6736(03)12713-4
[3] M. E. O’Rourke, “The Prostate-Specific Antigen Screening Conundrum Examining the Evidence,” Seminars in Oncology Nursing, Vol. 27, No. 4, 2011, pp. 251-259.doi:10.1016/j.soncn.2011.07.003
[4] V. A. Moyer, “Screening for Prostate Cancer: US Preventive Services Task Force Recommendation Statement,” Annals of Internal Medicine, 21 May 2012.
[5] J. Lovgren, T. Piironen and C. Overmo, “Production of Recombinant PSA and HK2 and Analysis of Their Immunologic Cross-Reactivity,” Biochemical and Biophysical Research Communications, Vol. 213, No. 3, 1995, pp. 888-895. doi:10.1006/bbrc.1995.2212
[6] M. C. Wang, L. D. Papsidero, M. Kuriyama, L. A. Valenzuela, et al., “Prostate Antigen: A New Potential Marker for Prostatic Cancer,” The Prostate, Vol. 2, No. 1, 1981, pp. 89-96. doi:10.1002/pros.2990020109
[7] C. A. Borgono, I. P. Michael and E. P. Diamandis, “Human Tissue Kallikreins: Physiologic Roles and Applications in Cancer,” Molecular Cancer Research, Vol. 2, No. 5, 2004, pp. 257-280.
[8] P. H. Riegman, R. J. Vlietstra, J. A. van der Korput, A. O. Brinkmann and J. Trapman, “The Promoter of the Prostate-Specific Antigen Gene Contains a Functional Androgen Responsive Element,” Molecular Endocrinology, Vol. 5, No. 12, 1991, pp. 1921-1930.doi:10.1210/mend-5-12-1921
[9] N. Zarghami, L. Grass, E. R. Sauter and E. P. Diamandis, “Prostate-Specific Antigen in Serum during the Menstrual Cycle,” Clinical Chemistry, Vol. 43, No. 10, 1997, pp. 1862-1867.
[10] P. Murtha, D. J. Tindall and C. Y. Young, “Androgen Induction of a Human Prostate-Specific Kallikrein, hKLK2: Characterization of an Androgen Response Element in the 5’ Promoter Region of the Gene,” Biochemistry, Vol. 32, No. 25, 1993, pp. 6459-6464.doi:10.1021/bi00076a020
[11] M. E. O’Rourke, “The Prostate-Specific Antigen Screening Conundrum Examining the Evidence,” Seminars in Oncology Nursing, Vol. 27, No. 4, 2011, pp. 251-259.doi:10.1016/j.soncn.2011.07.003
[12] M. G. Lawrence, J. Lai and J. A. Clements, “Kallikreins on Steroids Structure, Function, & Hormonal Regulation of Prostate-Specific Antigen & the Extended Kallikrein Locus,” Endocrine Reviews, Vol. 31, No. 4, 2010, pp. 407-446. doi:10.1210/er.2009-0034
[13] A. P. Cumming, S. N. Hopmans, S. Vukmirovic-Popovic and W. C. Duivenvoorden, “PSA Affects Prostate Cancer Cell Invasion in Vitro & Induces an Osteoblastic Phenotype in Bone in Vivo,” Prostate Cancer and Prostatic Diseases, Vol. 14, No. 4, 2011, pp. 286-294.doi:10.1038/pcan.2011.34
[14] P. Saxena, M. Trerotola, T. Wang, J. Li, A. Sayeed, et al., “PSA Regulates Androgen Receptor Expression in Prostate Cancer Cells,” Prostate, 28 September 2011.doi:10.1002/pros.21482
[15] A. Y. Olsson, A. Bjartell, H. Lilja and A. Lundwall, “Expression of Prostate-Specific Antigen (PSA) and Human Glandular Kallikrein 2 (hK2) in Ileum and Other Extraprostatic Tissues,” International Journal of Cancer, Vol. 113, No. 2, 2005, pp. 290-297. doi:10.1002/ijc.20605
[16] H. Lilja, J. Oldbing, G. Rannevik and C. B. Laurell, “Seminal Vesicle-Secreted Proteins and Their Reactions during Gelation and Liquefaction of Human of Human Semen,” Journal of Clinical Investigation, Vol. 80, No. 2, 1987, pp. 281-185. doi:10.1172/JCI113070
[17] W. Sieh, K. L. Edwards, A. L. Fitzpatrick, S. L. Srinouanprachanh, F. M. Farin, et al., “Genetic Susceptibility to Prostate Cancer: Prostate-Specific Antigen and Its Interaction with the Androgen Receptor,” Cancer Causes Control, Vol. 17, No. 2, 2006, pp. 187-197.doi:10.1007/s10552-005-0454-8
[18] W. Xue, R. A. Irvine, M. C. Yu, R. K. Ross, G. A. Coetzee and S. A. Ingles, “Susceptibility to Prostate Cancer: Interaction between Genotypes at the Androgen Receptor and Prostate-Specific Antigen Loci,” Cancer Research, Vol. 60, 2000, pp. 839-841.
[19] K. L. Penney, F. R. Schumacher, P. Kraft, L. A. Mucci, H. D. Sesso, J. Ma, Y. Niu, J. K. Cheong, D. J. Hunter, M. J. Stampfer and S. I. Hsu, “Association of KLK3 (PSA) Genetic Variants with Prostate Cancer Risk and PSA Levels,” Carcinogenesis, Vol. 32, No. 6, 2011, pp. 853- 859. doi:10.1093/carcin/bgr050
[20] S. A. Williams, P. Singh, J. T. Isaacs and S. R. Denmeade, “Does PSA Play a Role as a Promoting Agent during the Initiation and/or Progression of Prostate Cancer,” The Prostate, Vol. 67, No. 3, 2007, pp. 312-329.
[21] D. Thapa and R. Ghosh, “Antioxidants for Prostatecancer Chemoprevention: Challenges and Opportunities,” Biochemical Pharmacology, Vol. 83, No. 10, 2012, pp. 1319-1330. doi:10.1016/j.bcp.2011.12.027
[22] M. M. Webber, A. Waghray and D. Bello, “Prostate-Specific Antigen, a Serine Protease, Facilitates Human Prostate Cancer Cell Invasion,” Clinical Cancer Research, Vol. 1, 1995, pp. 1089-1094.
[23] P. Cohen, H. C. Graves, D. M. Peehl, M. Kamarei, et al., “Prostate-Specific Antigen (PSA) Is an Insulin-like Growth Factor Binding Protein-3 Protease found in Seminal Plasma,” The Journal of Clinical Endocrinology & Me- tabolism, Vol. 75, No. 4, 1992, pp. 1046-1053.doi:10.1210/jc.75.4.1046
[24] R. Pandey, N. Patil and M. Rao. “Proteases and Protease Inhibitors: Implications in Antitumorigenesis and Drug Development,” International Journal of Human Genetics, Vol. 7. No. 1, 2007, pp. 67-82.
[25] L. G. Wang, X. M. Liu, W. Kreis and D. R. Budman, “Down Regulation of Prostate-Specific Antigen Expression by Finasteride through Inhibition of Complex Formation between Androgen Receptor and Steroid Receptor Binding Consensus in the Promoter of the PSA Gene in LNCaP Cells,” Cancer Research, Vol. 57, No. 4, 1997, pp. 714-719.
[26] D. M. Sutkowski, R. L. Goode, J. Banial, C. Teater, et al., “Growth Regulation of Prostatic Stromal Cells by Prostate-Specific Antigen,” Journal of the National Cancer Institute, Vol. 91, No. 19, 1999, pp. 1663-1669.doi:10.1093/jnci/91.19.1663
[27] S. D. Cramer, Z. Chen and D. M. Peehl, “Prostate-Spe- cific Antigen Cleaves Parathyroid Hormone-Related Protein in the PTH-like Domain: Inactivation of PTHrP-Stimulated cAMP Accumulation in Mouse Osteoblasts,” Journal of Urology, Vol. 156, No. 2, 1996, pp. 526-531.doi:10.1016/S0022-5347(01)65919-6
[28] T. L. Veveris-Lowe, M. G. Lawrence, R. L. Collard, L. Bui, A. C. Heringtaon, et al., “Kallikrein 4 (hK4) and Prostate-Specific Antigen (PSA) Are Associated with the Loss of E-Cadherin and an Epithelial-Mesenchymal Transition (EMT)-like Effect in Prostate Cancer Cells,” Endocrine-Related Cancer, Vol. 12, 2005, pp. 631-643.doi:10.1677/erc.1.00958
[29] A. M. LeBeau, M. Kostova, C. S. Craik and S. R. Denmeade, “Prostate-Specific Antigen an Overlooked Candidate for the Targeted Treatment and Selective Imaging of Prostate Cancer,” The Journal of Biological Chemistry, Vol. 391, No. 4, 2010, pp. 333-343.doi:10.1515/bc.2010.044
[30] J. T. Lin, J. S. Wang, B. P. Jiann, C. C. Yu, et al., “Correlation of p53 Protein Accumulation and Bcl-2 Overexpression with Histopathological Features in Prostatic Cancer,” Journal of the Formosan Medical Association, Vol. 104, No. 11, 2005, pp. 864-867.
[31] Y. Niu, S. Yeh, H. Miyamoto, G. Li, S. Altuwaijri, J. Yuan, R. Han, T. Ma, H. C. Kuo and C. Chang, “Tissue Prostate-Specific Antigen Facilitates Refractory Prostate Tumor Progression via Enhancing ARA70-Regulated Androgen Receptor Transactivation,” Cancer Research, Vol. 68, No. 17, 2008, pp. 7110-7119.doi:10.1158/0008-5472.CAN-07-6507
[32] A. H. Fortier, J. W. Holaday, H. Liang, C. Dey, et al., “Recombinant Prostate-Specific Antigen Inhibits Angiogenesis in Vitro and in Vivo,” The Prostate, Vol. 56, No. 3, 2003, pp. 212-219. doi:10.1002/pros.10256
[33] H. Yu, E. P. Diamandis, N. Zarghami and L. Grass, “Induction of Prostate Specific Antigen Production by Steroids and Tamoxifen in Breast Cancer Cell Lines,” Breast Cancer Research and Treatment, Vol. 32, No. 3, 1994, pp. 291-300. doi:10.1007/BF00666006
[34] C. B. J. M. Cluetjens, K. Steketee, C. C. E. M. van Eekelen, J. A. G. M. van der Korput, et al., “Both Androgen Receptor and Glucocorticoid Receptor Are Able to Induce Prostate-Specific Antigen Expression, but Differ in Their Growth Stimulating Properties of LNCaP Cells,” Endocrinology, Vol. 138, No. 12, 1997, pp. 5293-5300.doi:10.1210/en.138.12.5293
[35] H. Yu, E. P. Diamandis, N. Zarghami and L. Grass, “Induction of Prostate-Specific Antigen Production by Steroids and Tamoxifen in Breast Cancer Cell Lines,” Breast Cancer Research and Treatment, Vol. 32, No. 3, 1994, pp. 291-300. doi:10.1007/BF00666006
[36] C. Wang, F. Yeung, P. C. Liu, A. M. Attar, J. Geng, L. W. K. Chung, et al., “Identification of a Novel Transcription Factor, GAGATA-Binding Protein, Involved in Androgen-Mediated Expression of Prostate-Specific Antigen,” The Journal of Biological Chemistry, Vol. 278, No. 34, 2003, pp. 32423-32430. doi:10.1074/jbc.M207862200
[37] J. A. R. de Winter, P. J. A. Janssen, H. M. E. B. Sleddens, M. C. T. Verleun-Mooijman, et al., “Androgen Receptor Status in Localized and Locally Progressive Hormone Refractory Human Prostate Cancer,” American Journal of Pathology, Vol. 144, 1994, pp. 735-746.
[38] C. D. Chen, D. S. Welsbie, C. Tran, S. H. Baek, et al., “Molecular Determinants of Resistance to Antiandrogen Therapy,” Nature Medicine, Vol. 10, 2004, pp. 33-39.doi:10.1038/nm972
[39] S. Koochekpour, “Androgen Receptor Signaling and Mutations in Prostate Cancer,” Asian Journal of Andrology, Vol. 12, No. 5, 2010, pp. 639-657. doi:10.1038/aja.2010.89
[40] S. A. Williams, C. A. Jelinek, I. Litvinov, R. J. Cotter, J. T. Isaacs and S. R. Denmeade, “Enzymatically Active Prostate-Specific Antigen Promotes Growth of Human Prostate Cancers,” The Prostate, Vol. 71, No. 15, 2011, pp. 1595-1607. doi:10.1002/pros.21375
[41] E. S. Orwoll, C. M. Nielson, F. Labrie, E. Barrett-Connor, J. A. Cauley, et al., “Osteoporotic Fractures in Men (MrOS) Research Group. Evidence for Geographical and Racial Variation in Serum Sex Steroid Levels in Older Men,” The Journal of Clinical Endocrinology & Metabolism, Vol. 95, No. 10, 2010, pp. E151-60.doi:10.1210/jc.2009-2435
[42] H. J. Litman, S. Bhasin, C. L. Link, A. B. Araujo and J. B. McKinlay, “Serum Androgen Levels in Black, Hispanic, and White Men,” The Journal of Clinical Endocrinology & Metabolism, Vol. 91, No. 11, 2006, pp. 4326-4334.doi:10.1210/jc.2006-0037
[43] W. S. Kubricht 3rd, B. J. Williams, T. Whatley, P. Pinckard, J. A. Eastham, “Serum Testosterone Levels in African-American and White Men Undergoing Prostate Biopsy,” Urology, Vol. 54, No. 6, 1999, pp. 1035-1038.doi:10.1016/S0090-4295(99)00290-3
[44] S. M. Harman, E. J. Metter, J. D. Tobin, J. Pearson and M. R. Blackman, “Longitudinal Effects of Aging on Serum Total and Free Testosterone Levels in Healthy Men. Baltimore Longitudinal Study of Aging,” The Journal of Clinical Endocrinology & Metabolism, Vol. 86, No. 2, 2001, pp. 724-731. doi:10.1210/jc.86.2.724
[45] J. P. Deslypere and A. Vermeulen, “Leydig Cell Function in Normal Men: Effect of Age, Life-Style, Residence, Diet, and Activity,” The Journal of Clinical Endocrinology & Metabolism, Vol. 59, No. 5, 1984, pp. 955-962.doi:10.1210/jcem-59-5-955
[46] S. P. Balk, Y. J. Ko and G. J. Bubley, “Biology of Prostate-Specific Antigen,” Journal of Clinical Oncology, Vol. 21, No. 2, pp. 383-391. doi:10.1200/JCO.2003.02.083
[47] P. Tang, W. Du, K. Xie, J. Fu, H. Chen, W. Yang and J. W. Moul, “Characteristics of Baseline PSA and PSA Velocity in Young Men without Prostate Cancer: Racial Differences,” The Prostate, Vol. 72, No. 2, pp. 173-80.doi:10.1002/pros.21418
[48] L. C. Chung, K. H. Tsui, T. H. Feng, S. L. Lee, P. L. Chang and H. H. Juang, “Curcumin Provides Potential Protection against the Activation of Hypoxia and Prolyl 4-Hydroxylase Inhibitors on Prostate-Specific Antigen Expression in Human Prostate Carcinoma Cells,” Molecular Nutrition & Food Research, Vol. 55, No. 11, 2011, pp. 1666-1676. doi:10.1002/mnfr.201100328
[49] C. P. Chuu, R. Y. Chen, J. M. Kokontis, R. A. Hiipakka and S. Liao, “Suppression Androgen Receptor Signaling Prostate Specific Antigen Expression by Epigallocatechin-3-Gallate Different Progression Stages LNCaP Prostate Cancer,” Cancer Letters, Vol. 275, No. 1, 2009, pp. 86-92. doi:10.1016/j.canlet.2008.10.001
[50] Y. Zhang, A. A. Shaik, C. Xing, Y. Chai, L. Li, J. Zhang, W. Zhang, S. H. Kim, J. Lü and C. Jiang, “A Synthetic Decursin Analog with Increased in Vivo Stability Suppresses Androgen Receptor Signaling in Vitro and in Vivo,” Investigational New Drugs, 2011.doi:10.1007/s10637-011-9738-x
[51] S. Lehmann, J. O’Kelly, T. Kumagai, J. C. Desmond, M. Pervan, W. H. McBride, M. Kizaki and H. P. Koeffler, “Capsaicin, a Component of Red Peppers, Inhibits the Growth of Androgen-Independent, p53 Mutant Prostate Cancer Cells,” Cancer Research, Vol. 66, No. 6, 2006, pp. 3222-3229.doi:10.1158/0008-5472.CAN-05-0087
[52] Reem Smoum, Abraham Rubinstein, Valery M. Dembitsky, and Morris Srebnik, “Boron Containing Compounds as Protease Inhibitors,” 2012.
[53] A. M. LeBeau, M. Kostova, C. S. Craik and S. R. Denmeade, “Prostate-Specific Antigen: An Overlooked Candidate for the Targeted Treatment and Selective Imaging of Prostate Cancer,” Biological Chemistry, 2010, Vol. 391, No. 4, pp. 333-343. doi:10.1515/bc.2010.044
[54] M. R. Goldstein and L. Mascitelli, “Regarding Prostate-Specific Antigen: Let’s Not Shoot the Messenger,” QJM, Vol. 105, No. 2, 2012, pp. 207-210.doi:10.1093/qjmed/hcr202
[55] P. Gazzerro, et al. “Pharmacological Actions of Statins: A Critical Appraisal in the Management of Cancer,” Pharmacological Reviews, Vol. 64, No. 1, 2012, pp. 102-146.doi:10.1124/pr.111.004994
[56] I. M. Thompson, P. J. Goodman, C. M. Tangen, M. S. Lucia, G. J. Miller, L. G. Ford, M. M. Lieber, R. D. Cespedes, J. N. Atkins, S. M. Lippman, S. M. Carlin, A. Ryan, C. M. Szczepanek, J. J. Crowley and C. A. Coltman Jr., “The Influence of Finasteride on the Development of Prostate Cancer,” The New England Journal of Medicine, Vol. 349, No. 3, 2003, pp. 215-224. doi:10.1056/NEJMoa030660
[57] G. L. Andriole, D. G. Bostwick, O. W. Brawley, L. G. Gomella, M. Marberger, F. Montorsi, et al., “Effect of Dutasteride on the Risk of Prostate Cancer,” The New England Journal of Medicine, Vol. 362, 2010, pp. 1192- 1202. doi:10.1056/NEJMoa0908127
[58] F. Azzouni and J. Mohler, “Role of 5α-Reductase Inhibitors in Prostate Cancer Prevention and Treatment,” Urology, 23 March 2012. doi:10.1016/j.urology.2012.01.024
[59] M. R. Theoret, Y. M. Ning, J. J. Zhang, R. Justice, P. Keegan and R. Pazdur, “The Risks and Benefits of 5α-Reductase Inhibitors for Prostate-Cancer Prevention,” The New England Journal of Medicine, Vol. 365, No. 2, 2011, pp. 97- 99. doi:10.1056/NEJMp1106783
[60] A. H. Fortier, B. J. Nelson, D. K. Grella and J. W. Holaday, “Antiangiogenic Activity of Prostate-Specific Antigen,” Journal of the National Cancer Institute, Vol. 91, 1999, pp. 1635-1640. doi:10.1093/jnci/91.19.1635
[61] T. Liu, L. Y. Wu, M. Kazak and C. E. Berkman, “Novel Small Molecule Inhibitors for Prostate-Specific Antigen,” The Prostate, Vol. 68, No. 9, 2008, pp. 955-964.doi:10.1002/pros.20753
[62] S. Altuwaijri, H. K. Lin, K. H. Chuang, W. J. Lin, S. Yeh, L. A. Hanchett, M. M. Rahman, H. Y. Kang, M. Y. Tsai, Y. Zhang, L. Yang and C. Chang, “Interruption of Nuclear Factor Kappab Signaling by the Androgen Receptor Facilitates 12-O-Tetradecanoylphorbolacetate-Induced A-poptosis in Androgen-Sensitive Prostate Cancer LNCaP Cells,” Cancer Research, Vol. 63, No. 21, 2003, pp. 7106-7112.

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.