Altered expression of farnesyl pyrophosphate synthase in prostate cancer: evidence for a role of the mevalonate pathway in disease progression?
- 312 Downloads
Preclinical studies demonstrated effects of drugs inhibiting the mevalonate pathway including nitrogen-containing bisphosphonates (N-BPs) and statins on tumor growth and progression. The exact role of this pathway in prostate cancer (PC) has not been identified yet. Herein, we evaluate the expression of farnesyl pyrophosphate synthase (FPPS), the key enzyme of the mevalonate pathway, in PC.
Patients and methods
Prostate cancer (PC) and benign prostate tissue of 114 men who underwent radical prostatectomy were constructed to a tissue microarray. Immunohistochemical staining of FPPS was quantified by the Remmele/Stegner immunoreactivity-score. Patients’ clinical follow-up was assessed. IRS was correlated to pathological and clinical data. The impact of FPPS expression on clinical course was assessed univariate and multivariate.
Mean IRS in PC and benign tissue was 5.7 (95% CI 5.0–6.5) and 2.6 (2.1–3.0, p < 0.0001). Mean IRS in PC tissue of patients with organ-confined and locally advanced disease (pT ≥ 3) was 5.09 (4.22–5.96) and 6.87 (5.57–8.17, p = 0.035). IRS of PC tissue significantly correlated with Gleason score (p = 0.03). Patients with PC tissue IRS >3 showed shorter recurrence-free survival compared to the remaining (p = 0.01). Increased FPPS expression is an independent risk factor for early biochemical recurrence (p = 0.032).
This is the first study on FPPS in PC specimens. The association of FPPS with established histopathological risk parameters and biochemical recurrence implicates a contribution of the mevalonate pathway to PC progression. Further functional analysis is required to explore the role of this pathway in PC and to investigate whether FPPS expression affects the response of PC cells to N-BPs.
KeywordsProstate cancer Bisphosphonates Farnesyl pyrophosphate synthase Zoledronic acid Mevalonate pathway
This work received external funding (SZOM-002-grant; Novartis Institutes for BioMedical Research). We thank Hannes Schramm for graphical assistance.
Conflict of interest
- 3.Luckman SP, Hughes DE, Coxon FP, Graham R, Russell G, Rogers MJ (1998) Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res 13(4):581–589. doi: 10.1359/jbmr.19184.108.40.2061 PubMedCrossRefGoogle Scholar
- 9.Hamilton RJ, Banez LL, Aronson WJ, Terris MK, Platz EA, Kane CJ, Presti JC Jr, Amling CL, Freedland SJ (2010) Statin medication use and the risk of biochemical recurrence after radical prostatectomy: results from the shared equal access regional cancer hospital (SEARCH) database. Cancer 116(14):3389–3398. doi: 10.1002/cncr.25308 PubMedCrossRefGoogle Scholar
- 12.Mottet N, Bellmunt J, Bolla M, Joniau S, Mason M, Matveev V, Schmid HP, Van der Kwast T, Wiegel T, Zattoni F, Heidenreich A (2011) EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol 59(4):572–583. doi: 10.1016/j.eururo.2011.01.025 PubMedCrossRefGoogle Scholar
- 13.Gnant M, Mlineritsch B, Schippinger W, Luschin-Ebengreuth G, Postlberger S, Menzel C, Jakesz R, Seifert M, Hubalek M, Bjelic-Radisic V, Samonigg H, Tausch C, Eidtmann H, Steger G, Kwasny W, Dubsky P, Fridrik M, Fitzal F, Stierer M, Rucklinger E, Greil R, Marth C (2009) Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 360(7):679–691. doi: 10.1056/NEJMoa0806285 PubMedCrossRefGoogle Scholar
- 19.Marra M, Salzano G, Leonetti C, Tassone P, Scarsella M, Zappavigna S, Calimeri T, Franco R, Liguori G, Cigliana G, Ascani R, La Rotonda MI, Abbruzzese A, Tagliaferri P, Caraglia M, De Rosa G (2011) Nanotechnologies to use bisphosphonates as potent anticancer agents: the effects of zoledronic acid encapsulated into liposomes. Nanomedicine. doi: 10.1016/j.nano.2011.03.004 PubMedGoogle Scholar
- 25.Notarnicola M, Messa C, Cavallini A, Bifulco M, Tecce MF, Eletto D, Di Leo A, Montemurro S, Laezza C, Caruso MG (2004) Higher farnesyl diphosphate synthase activity in human colorectal cancer inhibition of cellular apoptosis. Oncology 67(5–6):351–358. doi: 10.1159/000082918 PubMedCrossRefGoogle Scholar
- 28.Li J, Herold MJ, Kimmel B, Muller I, Rincon-Orozco B, Kunzmann V, Herrmann T (2009) Reduced expression of the mevalonate pathway enzyme farnesyl pyrophosphate synthase unveils recognition of tumor cells by Vγ9Vδ2 T cells. J Immunol 182(12):8118–8124. doi: 10.4049/jimmunol.0900101 PubMedCrossRefGoogle Scholar
- 29.Riddle MK, Lockhart AC, Sorscher SM (2010) Complete radiographic response to zoledronic acid therapy in a patient with bony metastatic urothelial carcinoma: a case report. World J Oncol 1(1):208–209Google Scholar