Biomed Res Int. 2013;2013:409179.

A comparison of the biological features of prostate cancer with (PSA+, PSMA+) profile according to RKIP.

Ben Jemaa A1, Bouraoui Y1, Sallami S2, Nouira Y2, Oueslati R1.

1Unit of Immunology and Microbiology Environmental and Carcinogenesis (IMEC), Faculty of Sciences of Bizerte, University of Carthage, Zarzouna 7021; 2Department of Urology, Hospital of La Rabta, Tunis 1007, Tunisia.

ABSTRACT

Purpose. To investigate differences in the biological features of the most immunoexpressed prostate cancer (PC) profiles (PSA+, PSMA+) according to the RKIP. Methods. 19 PC with dominant Gleason grade ≥8 were studied. Expression of PSA, PSMA, RKIP, Raf-1, MEK-1, ERK-1, ERK-2, p-Akt (T308), p-Akt (S473), NF-κB p50, and NF-κBp65 were detected immunohistochemically. Results. Loss of RKIP in the most immunoexpressed PC (PSA+, PSMA+) profile was associated with increased levels of PSA and PSMA expression. Intensities of immunoreactions to PSA and PSMA were higher in cancer cells negative for RKIP (12.51 ± 1.6 and 34.95 ± 1.92) compared to those positive for RKIP (4.68 ± 1.11 and 28.56 ± 0.91). In parallel, missing RKIP expression in PC patients with PSA+, PSMA+ profile was connected with increased components of both Raf-1/MEK/ERK and NF-κB (p65/p50), whereas Akt is activated independently of RKIP. Conclusions. Although characterized by the same (PSA+, PSMA+) profile, PC phenotype missing the RKIP related to invasive potential and greater biological aggressiveness reflected in overexpression of components of Raf-1/MEK/ERK and NF-κB (p65/p50) in which Akt is activated independently of RKIP. Taking into account the PC phenotypes according to RKIP among PSA-PSMA profiles may improve distinguishing them from cancers that will become more aggressive and therefore adapt the therapeutic strategies in those patients.

PMID: 23991415

 

SUPPLEMENT

Accumulating pieces of evidences indicate that RKIP expression induces several of the characteristics generally associated with prostate cancerous growth and spread. (1) Prostate specific antigen (PSA) and prostate specific membrane antigen (PSMA) have been identified as the most promising biomarkers in diagnosis and treatment of prostate cancer (PC). (2) We have previously showed that PSA and PSMA are often coexpressed in human cancerous prostate. (3) At present, biological features and consequences of this mostly immunoexpressed prostate cancer profile (PSA+,PSMA+) in disease outcome are largely unknown. To address these questions, we investigate the components of Raf-1/MEK/ERK, NF-κB (p50/p65), and Akt (T308/S473) pathways in conjunction with PSA and PSMA expression according to RKIP status in human cancerous prostate with (PSA+,PSMA+) profile.

The Gleason score is widely accepted as the standard for histologic grading of prostate malignancies. However, the scores of individual tumors, including the index tumor, often do not agree with this overall score. (4) Therefore, it is an urgent need for more accurate tools that provide greater prognostic significance than Gleason grade determination. Although our PC cases that coexpressed PSA and PSMA are mostly poorly differentiated adenocarcinoma (Gleason score ≥ 8), they reacted differently with RKIP. In fact, some of PC patients were reflected by the expression of RKIP, whereas in others it is reflected by the loss of this protein. Interestingly, among (PSA+,PSMA+) PC profile, loss of RKIP leads to upregulation of Raf-1/ERK and NF-κB pathways which subsequently stimulate PSA and PSMA expression. Nevertheless, Akt (T308/S473) is activated independently to RKIP status.

Although each pathway is conceptually linear, Raf-1/MEK/ERK, NF-κB, and Akt pathways are often coordinately deregulated toward hormone-refractory PC and contribute to their more malignant or aggressive phenotype. (5) On the basis of the above results, it seems that according to RKIP status, our PC patients with (PSA+,PSMA+) profile could exhibit the feature of two different PC phenotypes: an androgen-dependent phenotype for PC patients keeping the RKIP and an androgen-independent phenotype for those missing the RKIP.

Taken together, our study supports the heterogeneity and the complex clonal progression of PC disease. It is possible that this later PC phenotype might reflect a subpopulation of prostate tumor that will eventually escape hormonal control and relapse to androgen-independent state that is basically lethal. Beyond the potential role of RKIP in PC progression, analysis of RKIP status based on PSMA-PSA prostate profiles could potentially pinpoint group’s prostate patients into clinically relevant categories and subsequently can be valuable for therapeutic approaches in the anticancer treatment of prostate cancer.

Awatef Ben Jemaa-fig1

References

  1. J. Klysik, S. J. Theroux, J. M. Sedivy, J. S. Moffit, and K. Boekelheide, “Signaling crossroads: the function of Raf kinase inhibitory protein in cancer, the central nervous system and reproduction,” Cellular Signalling, vol. 20, pp. 1–9, 2008.
  2. A. K. Rajasekaran, G. Anilkumar, and J. J. Christiansen, “Is prostate-specific membrane antigen a multifunctional protein?” American Journal of Physiology, vol. 288, no. 5, pp. C975–C981, 2005.
  3. A. Ben Jemaa, Y. Bouraoui, S. Sallami et al., “Co-expression and impact of prostate specific membrane antigen and prostate specific antigen in prostatic pathologies,” Journal of Experimental and Clinical Cancer Research, vol. 29, pp. 171–179, 2010.
  4. 4.R. Arora , M.O. Koch , J.N. Eble , T.M. Ulbright , L. Li , L. Cheng, “Heterogeneity of Gleason grade in multifocal adenocarcinoma of the prostate,” Cancer, vol. 100, pp. 2362-2366, 2004.
  5. E. G. Bluemn and P. S. Nelson, “The androgen/androgen receptor axis in prostate cancer,” Current Opinion in Oncology, vol. 24, no. 3, pp. 251–257, 2012.

 

Acknowledgment: This work is supported by Grants from Ministry of Higher Education and Scientific Research in Tunisia.

Contact: Prof. Ridha OUESLATI (E-mail: oueslatiridha12@hotmail.fr ; Phone: + 216 97 415 031) or Dr. Awatef BEN JEMAA (E-mail: benjemaa_awatef@yahoo.fr ; Phone: +216 20 992 854 ) Unit of Immunology and Microbiology Environmental and Carcinogenesis (IMEC), Faculty of Sciences of Bizerte, 7021, Zarzouna, University of Carthage, Tunisia. Fax: +216 72 590 566.

Awatef

Dr. Awatef BEN JEMAA

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