Top

BMC Cancer

Published in:

Open Access 01-12-2006 | Research article

Zoledronic acid treatment impairs protein geranyl-geranylation for biological effects in prostatic cells

Authors: M Goffinet, M Thoulouzan, A Pradines, I Lajoie-Mazenc, Carolyn Weinbaum, JC Faye, S Séronie-Vivien

Published in: BMC Cancer | Issue 1/2006

Abstract

Background

Nitrogen-containing bisphosphonates (N-BPs) have been designed to inhibit osteoclast-mediated bone resorption. However, it is now accepted that part of their anti-tumor activities is related to interference with the mevalonate pathway.

Methods

We investigated the effects of zoledronic acid (ZOL), on cell proliferation and protein isoprenylation in two tumoral (LnCAP, PC-3,), and one normal established (PNT1-A) prostatic cell line. To assess if inhibition of geranyl-geranylation by ZOL impairs the biological activity of RhoA GTPase, we studied the LPA-induced formation of stress fibers. The inhibitory effect of ZOL on geranyl geranyl transferase I was checked biochemically. Activity of ZOL on cholesterol biosynthesis was determined by measuring the incorporation of ¹⁴C mevalonate in cholesterol.

Results

ZOL induced dose-dependent inhibition of proliferation of all the three cell lines although it appeared more efficient on the untransformed PNT1A. Whatever the cell line, 20 μM ZOL-induced inhibition was reversed by geranyl-geraniol (GGOH) but neither by farnesol nor mevalonate. After 48 hours treatment of cells with 20 μM ZOL, geranyl-geranylation of Rap1A was abolished whereas farnesylation of HDJ-2 was unaffected. Inhibition of Rap1A geranyl-geranylation by ZOL was rescued by GGOH and not by FOH. Indeed, as observed with treatment by a geranyl-geranyl transferase inhibitor, treatment of PNT1-A cells with 20 μM ZOL prevented the LPA-induced formation of stress fibers. We checked that in vitro ZOL did not inhibit geranyl-geranyl-transferase I. ZOL strongly inhibited cholesterol biosynthesis up to 24 hours but at 48 hours 90% of this biosynthesis was rescued.

Conclusion

Although zoledronic acid is currently the most efficient bisphosphonate in metastatic prostate cancer management, its mechanism of action in prostatic cells remains unclear. We suggest in this work that although in first intention ZOL inhibits FPPsynthase its main biological actitivity is directed against protein Geranylgeranylation.

Available only for authorised users

Rogers MJ, Gordon S, Benford HL, Coxon FP, Luckman SP, Monkkonen J, Frith JC: Cellular and molecular mechanisms of action of bisphosphonates. Cancer. 2000, 88: 2961-2978. 10.1002/1097-0142(20000615)88:12+<2961::AID-CNCR12>3.0.CO;2-L.CrossRefPubMed

Green JR, Clezardin P: Mechanisms of bisphosphonate effects on osteoclasts, tumor cell growth, and metastasis. Am J Clin Oncol. 2002, 25: S3-9. 10.1097/00000421-200212001-00002.CrossRefPubMed

Amin D, Cornell SA, Gustafson SK, Needle SJ, Ullrich JW, Bilder GE, Perrone MH: Bisphosphonates used for the treatment of bone disorders inhibit squalene synthase and cholesterol biosynthesis. J Lipid Res. 1992, 33: 1657-1663.PubMed

Bergstrom JD, Bostedor RG, Masarachia PJ, Reszka AA, Rodan G: Alendronate is a specific, nanomolar inhibitor of farnesyl diphosphate synthase. Arch Biochem Biophys. 2000, 373: 231-241. 10.1006/abbi.1999.1502.CrossRefPubMed

Thompson K, Dunford JE, Ebetino FH, Rogers MJ: Identification of a bisphosphonate that inhibits isopentenyl diphosphate isomerase and farnesyl diphosphate synthase. Biochem Biophys Res Commun. 2002, 290: 869-873. 10.1006/bbrc.2001.6289.CrossRefPubMed

van Beek E, Pieterman E, Cohen L, Lowik C, Papapoulos S: Farnesyl pyrophosphate synthase is the molecular target of nitrogen-containing bisphosphonates. Biochem Biophys Res Commun. 1999, 264: 108-111. 10.1006/bbrc.1999.1499.CrossRefPubMed

Benford HL, Frith JC, Auriola S, Monkkonen J, Rogers MJ: Farnesol and geranylgeraniol prevent activation of caspases by aminobisphosphonates: biochemical evidence for two distinct pharmacological classes of bisphosphonate drugs. Mol Pharmacol. 1999, 56: 131-140.PubMed

Luckman SP, Hughes DE, Coxon FP, Graham R, Russell G, Rogers MJ: Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res. 1998, 13: 581-589.CrossRefPubMed

Iguchi T, Miyakawa Y, Yamamoto K, Kizaki M, Ikeda Y: Nitrogen-containing bisphosphonates induce S-phase cell cycle arrest and apoptosis of myeloma cells by activating MAPK pathway and inhibiting mevalonate pathway. Cell Signal. 2003, 15: 719-727. 10.1016/S0898-6568(03)00007-X.CrossRefPubMed

10.

Fisher JE, Rogers MJ, Halasy JM, Luckman SP, Hughes DE, Masarachia PJ, Wesolowski G, Russell RG, Rodan GA, Reszka AA: Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro. Proc Natl Acad Sci U S A. 1999, 96: 133-138. 10.1073/pnas.96.1.133.CrossRefPubMedPubMedCentral

11.

Sawada K, Morishige K, Tahara M, Kawagishi R, Ikebuchi Y, Tasaka K, Murata Y: Alendronate inhibits lysophosphatidic acid-induced migration of human ovarian cancer cells by attenuating the activation of rho. Cancer Res. 2002, 62: 6015-6020.PubMed

12.

Denoyelle C, Hong L, Vannier JP, Soria J, Soria C: New insights into the actions of bisphosphonate zoledronic acid in breast cancer cells by dual RhoA-dependent and -independent effects. Br J Cancer. 2003, 88: 1631-1640. 10.1038/sj.bjc.6600925.CrossRefPubMedPubMedCentral

13.

Coxon FP, Helfrich MH, Van't Hof R, Sebti S, Ralston SH, Hamilton A, Rogers MJ: Protein geranylgeranylation is required for osteoclast formation, function, and survival: inhibition by bisphosphonates and GGTI-298. J Bone Miner Res. 2000, 15: 1467-1476.CrossRefPubMed

14.

Van Beek ER, Lowik CW, Papapoulos SE: Bisphosphonates suppress bone resorption by a direct effect on early osteoclast precursors without affecting the osteoclastogenic capacity of osteogenic cells: the role of protein geranylgeranylation in the action of nitrogen-containing bisphosphonates on osteoclast precursors. Bone. 2002, 30: 64-70. 10.1016/S8756-3282(01)00655-X.CrossRefPubMed

15.

Oades GM, Senaratne SG, Clarke IA, Kirby RS, Colston KW: Nitrogen containing bisphosphonates induce apoptosis and inhibit the mevalonate pathway, impairing Ras membrane localization in prostate cancer cells. J Urol. 2003, 170: 246-252. 10.1097/01.ju.0000070685.34760.5f.CrossRefPubMed

16.

Senaratne SG, Mansi JL, Colston KW: The bisphosphonate zoledronic acid impairs Ras membrane [correction of impairs membrane] localisation and induces cytochrome c release in breast cancer cells. Br J Cancer. 2002, 86: 1479-1486. 10.1038/sj.bjc.6600297.CrossRefPubMedPubMedCentral

17.

Virtanen SS, Vaananen HK, Harkonen PL, Lakkakorpi PT: Alendronate inhibits invasion of PC-3 prostate cancer cells by affecting the mevalonate pathway. Cancer Res. 2002, 62: 2708-2714.PubMed

18.

Saad F: Treatment of bone complications in advanced prostate cancer: rationale for bisphosphonate use and results of a phase III trial with zoledronic acid. Semin Oncol. 2002, 29: 19-27. 10.1053/sonc.2002.37418.CrossRefPubMed

19.

Smith MR, McGovern FJ, Zietman AL, Fallon MA, Hayden DL, Schoenfeld DA, Kantoff PW, Finkelstein JS: Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med. 2001, 345: 948-955. 10.1056/NEJMoa010845.CrossRefPubMed

20.

Boissier S, Ferreras M, Peyruchaud O, Magnetto S, Ebetino FH, Colombel M, Delmas P, Delaisse JM, Clezardin P: Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res. 2000, 60: 2949-2954.PubMed

21.

Lee MV, Fong EM, Singer FR, Guenette RS: Bisphosphonate treatment inhibits the growth of prostate cancer cells. Cancer Res. 2001, 61: 2602-2608.PubMed

22.

Lerner EC, Qian Y, Blaskovich MA, Fossum RD, Vogt A, Sun J, Cox AD, Der CJ, Hamilton AD, Sebti SM: Ras CAAX peptidomimetic FTI-277 selectively blocks oncogenic Ras signaling by inducing cytoplasmic accumulation of inactive Ras-Raf complexes. J Biol Chem. 1995, 270: 26802-26806. 10.1074/jbc.270.45.26802.CrossRefPubMed

23.

McGuire TF, Qian Y, Vogt A, Hamilton AD, Sebti SM: Platelet-derived growth factor receptor tyrosine phosphorylation requires protein geranylgeranylation but not farnesylation. J Biol Chem. 1996, 271: 27402-27407. 10.1074/jbc.271.44.27402.CrossRefPubMed

24.

Cussenot O, Berthon P, Berger R, Mowszowicz I, Faille A, Hojman F, Teillac P, Le Duc A, Calvo F: Immortalization of human adult normal prostatic epithelial cells by liposomes containing large T-SV40 gene. J Urol. 1991, 146: 881-886.PubMed

25.

Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D, Warren JT, Bokesch H, Kenney S, Boyd MR: New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst. 1990, 82: 1107-1112.CrossRefPubMed

26.

Awad AB, Williams H, Fink CS: Effect of phytosterols on cholesterol metabolism and MAP kinase in MDA-MB-231 human breast cancer cells. J Nutr Biochem. 2003, 14: 111-119. 10.1016/S0955-2863(02)00274-7.CrossRefPubMed

27.

Corey E, Brown LG, Quinn JE, Poot M, Roudier MP, Higano CS, Vessella RL: Zoledronic acid exhibits inhibitory effects on osteoblastic and osteolytic metastases of prostate cancer. Clin Cancer Res. 2003, 9: 295-306.PubMed

28.

Crick DC, Andres DA, Waechter CJ: Novel salvage pathway utilizing farnesol and geranylgeraniol for protein isoprenylation. Biochem Biophys Res Commun. 1997, 237: 483-487. 10.1006/bbrc.1997.7145.CrossRefPubMed

29.

Lobell RB, Liu D, Buser CA, Davide JP, DePuy E, Hamilton K, Koblan KS, Lee Y, Mosser S, Motzel SL, Abbruzzese JL, Fuchs CS, Rowinsky EK, Rubin EH, Sharma S, Deutsch PJ, Mazina KE, Morrison BW, Wildonger L, Yao SL, Kohl NE: Preclinical and clinical pharmacodynamic assessment of L-778,123, a dual inhibitor of farnesyl:protein transferase and geranylgeranyl:protein transferase type-I. Mol Cancer Ther. 2002, 1: 747-758.PubMed

30.

Holstein SA, Cermak DM, Wiemer DF, Lewis K, Hohl RJ: Phosphonate and bisphosphonate analogues of farnesyl pyrophosphate as potential inhibitors of farnesyl protein transferase. Bioorg Med Chem. 1998, 6: 687-694. 10.1016/S0968-0896(98)00034-0.CrossRefPubMed

31.

Ownby SE, Hohl RJ: Isoprenoid alcohols restore protein isoprenylation in a time-dependent manner independent of protein synthesis. Lipids. 2003, 38: 751-759.CrossRefPubMed

32.

Allal C, Favre G, Couderc B, Salicio S, Sixou S, Hamilton AD, Sebti SM, Lajoie-Mazenc I, Pradines A: RhoA prenylation is required for promotion of cell growth and transformation and cytoskeleton organization but not for induction of serum response element transcription. J Biol Chem. 2000, 275: 31001-31008. 10.1074/jbc.M005264200.CrossRefPubMed

33.

Dunford JE, Thompson K, Coxon FP, Luckman SP, Hahn FM, Poulter CD, Ebetino FH, Rogers MJ: Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther. 2001, 296: 235-242.PubMed

34.

Fisher JE, Rodan GA, Reszka AA: In vivo effects of bisphosphonates on the osteoclast mevalonate pathway. Endocrinology. 2000, 141: 4793-4796. 10.1210/en.141.12.4793.CrossRefPubMed

The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/6/60/prepub

Title: Zoledronic acid treatment impairs protein geranyl-geranylation for biological effects in prostatic cells
Authors: M Goffinet
M Thoulouzan
A Pradines
I Lajoie-Mazenc
Carolyn Weinbaum
JC Faye
S Séronie-Vivien
Publication date: 01-12-2006
Publisher: BioMed Central
Published in: BMC Cancer / Issue 1/2006
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/1471-2407-6-60

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2006

Polymorphisms in GSTT1, GSTM1, NAT1 and NAT2genes and bladder cancer risk in men and women

Weekly oxaliplatin, 5-fluorouracil and folinic acid (OXALF) as first-line chemotherapy for elderly patients with advanced gastric cancer: results of a phase II trial

Cell cycle regulation by the Wee1 Inhibitor PD0166285, Pyrido [2,3-d] pyimidine, in the B16 mouse melanoma cell line

Expression of chemokine receptor CXCR4 in esophageal squamous cell and adenocarcinoma

The fibrinolytic system facilitates tumor cell migration across the blood-brain barrier in experimental melanoma brain metastasis

Hidden chromosomal abnormalities in pleuropulmonary blastomas identified by multiplex FISH

Keynote webinar | Spotlight on antibody–drug conjugates in cancer