Zoledronic Acid Inhibits the RhoA-mediated Amoeboid Motility of Prostate Cancer Cells

Author(s): Laura Pietrovito, Giuseppina Comito, Matteo Parri, Elisa Giannoni, Paola Chiarugi, Maria Letizia Taddei*.

Journal Name: Current Cancer Drug Targets

Volume 19 , Issue 10 , 2019

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: The bisphosphonate Zoledronic acid (ZA) is a potent osteoclast inhibitor currently used in the clinic to reduce osteoporosis and cancer-induced osteolysis. Moreover, ZA exerts an anti-tumor effect in several tumors. Despite this evidence, the relevance of ZA in prostate cancer (PCa) is not completely understood.

Objective: To investigate the effect of ZA administration on the invasive properties of PC3 cells, which are characterised by RhoA-dependent amoeboid motility.

Methods: The effect of ZA administration on the in vitro invasive properties of PC3 cells was evaluated by cell migration in 3D collagen matrices, immunofluorescence and Boyden assays or transendothelial migration. Lung retention and colonization assays were performed to assess the efficacy of ZA administration in vivo.

Results: PC3 cells are characterised by RhoA-dependent amoeboid motility. We now report a clear inhibition of in vitro PC3 cell invasion and RhoA activity upon ZA treatment. Moreover, to confirm a specific role of ZA in the inhibition of amoeboid motility of PC3 cells, we demonstrate that ZA interferes only partially with PC3 cells showing a mesenchymal phenotype due to both treatment with conditioned medium of cancer associated fibroblasts or to the acquisition of chemoresistance. Furthermore, we demonstrate that ZA impairs adhesion to endothelial cells and the trans-endothelial cell migration, two essential properties characterising amoeboid motility and PC3 metastatic dissemination. In vivo experiments prove the ability of ZA to inhibit the metastatic process of PC3 cells as shown by the decrease in lung colonization.

Conclusion: This study demonstrates that ZA inhibits Rho-dependent amoeboid motility of PC3 cells, thus suggesting ZA as a potential therapy to impede the metastatic dissemination of PC3 cells.

Keywords: Prostate cancer, zoledronic acid, amoeboid motility, RhoA, metastasis, endothelium.

[1]
Coscia, M.; Quaglino, E.; Iezzi, M.; Curcio, C.; Pantaleoni, F.; Riganti, C.; Holen, I.; Mönkkönen, H.; Boccadoro, M.; Forni, G.; Musiani, P.; Bosia, A.; Cavallo, F.; Massaia, M. Zoledronic acid repolarizes tumour-associated macrophages and inhibits mammary carcinogenesis by targeting the mevalonate pathway. J. Cell. Mol. Med., 2010, 14(12), 2803-2815.
[2]
Saad, F. Role of bisphosphonates in non-metastatic prostate cancer. Lancet Oncol., 2014, 15(10), 1041-1042.
[3]
Song, Z.; Zhang, Y. Zoledronic acid treatment in advanced non-small cell lung cancer patients with bone metastases. Med. Oncol., 2014, 31(4), 898.
[4]
Laggner, U.; Lopez, J.S.; Perera, G.; Warbey, V.S.; Sita-Lumsden, A.; O’Doherty, M.J.; Hayday, A.; Harries, M.; Nestle, F.O. Regression of melanoma metastases following treatment with the n-bisphosphonate zoledronate and localised radiotherapy. Clin. Immunol., 2009, 131(3), 367-373.
[5]
El-Amm, J.; Aragon-Ching, J.B. Targeting Bone Metastases in Metastatic Castration-Resistant Prostate Cancer. Clin. Med. Insights Oncol., 2016, 10(Suppl. 1), 11-19.
[6]
Singh, T.; Kaur, V.; Kumar, M.; Kaur, P.; Murthy, R.S.; Rawal, R.K. The critical role of bisphosphonates to target bone cancer metastasis: an overview. J. Drug Target., 2015, 23(1), 1-15.
[7]
Morgan, G.J.; Davies, F.E.; Gregory, W.M.; Cocks, K.; Bell, S.E.; Szubert, A.J.; Navarro-Coy, N.; Drayson, M.T.; Owen, R.G.; Feyler, S.; Ashcroft, A.J.; Ross, F.; Byrne, J.; Roddie, H.; Rudin, C.; Cook, G.; Jackson, G.H.; Child, J.A.; Group, N.C.R.I.H.O.C.S. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet, 2010, 376(9757), 1989-1999.
[8]
Conte, P.; Coleman, R. Bisphosphonates in the treatment of skeletal metastases. Semin. Oncol., 2004, 31(5)(Suppl. 10), 59-63.
[9]
Zekri, J.; Mansour, M.; Karim, S.M. The anti-tumour effects of zoledronic acid. J. Bone Oncol., 2014, 3(1), 25-35.
[10]
Zameer, S.; Najmi, A.K.; Vohora, D.; Akhtar, M. Bisphosphonates: Future perspective for neurological disorders. Pharmacol. Rep., 2018, 70(5), 900-907.
[11]
Oades, G.M.; Senaratne, S.G.; Clarke, I.A.; Kirby, R.S.; Colston, K.W. Nitrogen containing bisphosphonates induce apoptosis and inhibit the mevalonate pathway, impairing Ras membrane localization in prostate cancer cells. J. Urol., 2003, 170(1), 246-252.
[12]
McCubrey, J.A.; Steelman, L.S.; Chappell, W.H.; Abrams, S.L.; Wong, E.W.; Chang, F.; Lehmann, B.; Terrian, D.M.; Milella, M.; Tafuri, A.; Stivala, F.; Libra, M.; Basecke, J.; Evangelisti, C.; Martelli, A.M.; Franklin, R.A. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim. Biophys. Acta, 2007, 1773(8), 1263-1284.
[13]
Denoyelle, C.; Hong, L.; Vannier, J.P.; 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(10), 1631-1640.
[14]
Adjei, A.A. Ras signaling pathway proteins as therapeutic targets. Curr. Pharm. Des., 2001, 7(16), 1581-1594.
[15]
Sahai, E.; Marshall, C.J. RHO-GTPases and cancer. Nat. Rev. Cancer, 2002, 2(2), 133-142.
[16]
Evers, E.E.; Zondag, G.C.; Malliri, A.; Price, L.S.; ten Klooster, J.P.; van der Kammen, R.A.; Collard, J.G. Rho family proteins in cell adhesion and cell migration. Eur. J. Cancer, 2000, 36(10), 1269-1274.
[17]
Parri, M.; Buricchi, F.; Giannoni, E.; Grimaldi, G.; Mello, T.; Raugei, G.; Ramponi, G.; Chiarugi, P. EphrinA1 activates a Src/focal adhesion kinase-mediated motility response leading to rho-dependent actino/myosin contractility. J. Biol. Chem., 2007, 282(27), 19619-19628.
[18]
Giannoni, E.; Taddei, M.L.; Parri, M.; Bianchini, F.; Santosuosso, M.; Grifantini, R.; Fibbi, G.; Mazzanti, B.; Calorini, L.; Chiarugi, P. EphA2-mediated mesenchymal-amoeboid transition induced by endothelial progenitor cells enhances metastatic spread due to cancer-associated fibroblasts. J. Mol. Med. (Berl.), 2013, 91(1), 103-115.
[19]
Taddei, M.L.; Parri, M.; Angelucci, A.; Onnis, B.; Bianchini, F.; Giannoni, E.; Raugei, G.; Calorini, L.; Rucci, N.; Teti, A.; Bologna, M.; Chiarugi, P. Kinase-dependent and -independent roles of EphA2 in the regulation of prostate cancer invasion and metastasis. Am. J. Pathol., 2009, 174(4), 1492-1503.
[20]
Taddei, M.L.; Parri, M.; Angelucci, A.; Bianchini, F.; Marconi, C.; Giannoni, E.; Raugei, G.; Bologna, M.; Calorini, L.; Chiarugi, P. EphA2 induces metastatic growth regulating amoeboid motility and clonogenic potential in prostate carcinoma cells. Mol. Cancer Res., 2011, 9(2), 149-160.
[21]
Comito, G.; Pons Segura, C.; Taddei, M.L.; Lanciotti, M.; Serni, S.; Morandi, A.; Chiarugi, P.; Giannoni, E. Zoledronic acid impairs stromal reactivity by inhibiting M2-macrophages polarization and prostate cancer-associated fibroblasts. Oncotarget, 2017, 8(1), 118-132.
[22]
Ippolito, L.; Marini, A.; Cavallini, L.; Morandi, A.; Pietrovito, L.; Pintus, G.; Giannoni, E.; Schrader, T.; Puhr, M.; Chiarugi, P.; Taddei, M.L. Metabolic shift toward oxidative phosphorylation in docetaxel resistant prostate cancer cells. Oncotarget, 2016.
[23]
Fiaschi, T.; Marini, A.; Giannoni, E.; Taddei, M.L.; Gandellini, P.; De Donatis, A.; Lanciotti, M.; Serni, S.; Cirri, P.; Chiarugi, P. Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay. Cancer Res., 2012, 72(19), 5130-5140.
[24]
Pietrovito, L.; Leo, A.; Gori, V.; Lulli, M.; Parri, M.; Becherucci, V.; Piccini, L.; Bambi, F.; Taddei, M.L.; Chiarugi, P. Bone marrow-derived mesenchymal stem cells promote invasiveness and transendothelial migration of osteosarcoma cells via a mesenchymal to amoeboid transition. Mol. Oncol., 2018, 12(5), 659-676.
[25]
Giannoni, E.; Bianchini, F.; Masieri, L.; Serni, S.; Torre, E.; Calorini, L.; Chiarugi, P. Reciprocal activation of prostate cancer cells and cancer-associated fibroblasts stimulates epithelial-mesenchymal transition and cancer stemness. Cancer Res., 2010, 70(17), 6945-6956.
[26]
Riganti, C.; Castella, B.; Kopecka, J.; Campia, I.; Coscia, M.; Pescarmona, G.; Bosia, A.; Ghigo, D.; Massaia, M. Zoledronic acid restores doxorubicin chemosensitivity and immunogenic cell death in multidrug-resistant human cancer cells. PLoS One, 2013, 8(4)e60975
[27]
Comito, G.; Giannoni, E.; Segura, C.P.; Barcellos-de-Souza, P.; Raspollini, M.R.; Baroni, G.; Lanciotti, M.; Serni, S.; Chiarugi, P. Cancer-associated fibroblasts and M2-polarized macrophages synergize during prostate carcinoma progression. Oncogene, 2014, 33(19), 2423-2431.
[28]
Reymond, N. Im, J.H.; Garg, R.; Vega, F.M.; Borda d’Agua, B.; Riou, P.; Cox, S.; Valderrama, F.; Muschel, R.J.; Ridley, A.J. Cdc42 promotes transendothelial migration of cancer cells through β1 integrin. J. Cell Biol., 2012, 199(4), 653-668.
[29]
Taddei, M.L.; Cavallini, L.; Ramazzotti, M.; Comito, G.; Pietrovito, L.; Morandi, A.; Giannoni, E.; Raugei, G.; Chiarugi, P. Stromal-induced downregulation of miR-1247 promotes prostate cancer malignancy. J. Cell. Physiol., 2018, 8274-8285.
[30]
Petrylak, D.P.; Tangen, C.M.; Hussain, M.H.; Lara, P.N.; Jones, J.A.; Taplin, M.E.; Burch, P.A.; Berry, D.; Moinpour, C.; Kohli, M.; Benson, M.C.; Small, E.J.; Raghavan, D.; Crawford, E.D. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N. Engl. J. Med., 2004, 351(15), 1513-1520.
[31]
Lipton, A.; Small, E.; Saad, F.; Gleason, D.; Gordon, D.; Smith, M.; Rosen, L.; Kowalski, M.O.; Reitsma, D.; Seaman, J. The new bisphosphonate, Zometa (zoledronic acid), decreases skeletal complications in both osteolytic and osteoblastic lesions: a comparison to pamidronate. Cancer Invest., 2002, 20(Suppl. 2), 45-54.
[32]
Rosen, L.S.; Gordon, D.; Kaminski, M.; Howell, A.; Belch, A.; Mackey, J.; Apffelstaedt, J.; Hussein, M.; Coleman, R.E.; Reitsma, D.J.; Seaman, J.J.; Chen, B.L.; Ambros, Y. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J., 2001, 7(5), 377-387.
[33]
Sackmann, E. How actin/myosin crosstalks guide the adhesion, locomotion and polarization of cells. Biochim. Biophys. Acta, 2015, 1853(11 Pt B), 3132-3142.
[34]
Wood, J.; Bonjean, K.; Ruetz, S.; Bellahcène, A.; Devy, L.; Foidart, J.M.; Castronovo, V.; Green, J.R. Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J. Pharmacol. Exp. Ther., 2002, 302(3), 1055-1061.
[35]
Ziebart, T.; Pabst, A.; Klein, M.O.; Kämmerer, P.; Gauss, L.; Brüllmann, D.; Al-Nawas, B.; Walter, C. Bisphosphonates: restrictions for vasculogenesis and angiogenesis: inhibition of cell function of endothelial progenitor cells and mature endothelial cells in vitro. Clin. Oral Investig., 2011, 15(1), 105-111.
[36]
Dieli, F.; Gebbia, N.; Poccia, F.; Caccamo, N.; Montesano, C.; Fulfaro, F.; Arcara, C.; Valerio, M.R.; Meraviglia, S.; Di Sano, C.; Sireci, G.; Salerno, A. Induction of gammadelta T-lymphocyte effector functions by bisphosphonate zoledronic acid in cancer patients in vivo. Blood, 2003, 102(6), 2310-2311.
[37]
Naoe, M.; Ogawa, Y.; Takeshita, K.; Morita, J.; Shichijo, T.; Fuji, K.; Fukagai, T.; Iwamoto, S.; Terao, S. Zoledronate stimulates gamma delta T cells in prostate cancer patients. Oncol. Res., 2010, 18(10), 493-501.
[38]
Santini, D.; Martini, F.; Fratto, M.E.; Galluzzo, S.; Vincenzi, B.; Agrati, C.; Turchi, F.; Piacentini, P.; Rocci, L.; Manavalan, J.S.; Tonini, G.; Poccia, F. In vivo effects of zoledronic acid on peripheral gammadelta T lymphocytes in early breast cancer patients. Cancer Immunol. Immunother., 2009, 58(1), 31-38.
[39]
Jiang, P.; Zhang, P.; Mukthavaram, R.; Nomura, N.; Pingle, S.C.; Teng, D.; Chien, S.; Guo, F.; Kesari, S. Anti-cancer effects of nitrogen-containing bisphosphonates on human cancer cells. Oncotarget, 2016, 7(36), 57932-57942.
[40]
Mani, J.; Vallo, S.; Barth, K.; Makarević, J.; Juengel, E.; Bartsch, G.; Wiesner, C.; Haferkamp, A.; Blaheta, R.A. Zoledronic acid influences growth, migration and invasive activity of prostate cancer cells in vitro. Prostate Cancer Prostatic Dis., 2012, 15(3), 250-255.
[41]
Taddei, M.L.; Giannoni, E.; Comito, G.; Chiarugi, P. Microenvironment and tumor cell plasticity: an easy way out. Cancer Lett., 2013, 341(1), 80-96.
[42]
Wolf, K.; Friedl, P. Molecular mechanisms of cancer cell invasion and plasticity. Br. J. Dermatol., 2006, 154(Suppl. 1), 11-15.
[43]
Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell, 2011, 144(5), 646-674.
[44]
Saad, F.; Gleason, D.M.; Murray, R.; Tchekmedyian, S.; Venner, P.; Lacombe, L.; Chin, J.L.; Vinholes, J.J.; Goas, J.A.; Chen, B.; Group, Z.A.P.C.S. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J. Natl. Cancer Inst., 2002, 94(19), 1458-1468.
[45]
Gnant, M.; Mlineritsch, B.; Luschin-Ebengreuth, G.; Kainberger, F.; Kässmann, H.; Piswanger-Sölkner, J.C.; Seifert, M.; Ploner, F.; Menzel, C.; Dubsky, P.; Fitzal, F.; Bjelic-Radisic, V.; Steger, G.; Greil, R.; Marth, C.; Kubista, E.; Samonigg, H.; Wohlmuth, P.; Mittlböck, M.; Jakesz, R. (ABCSG) A.B.A.C.C.S.G. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 5-year follow-up of the ABCSG-12 bone-mineral density substudy. Lancet Oncol., 2008, 9(9), 840-849.


Rights & PermissionsPrintExport Cite as


Article Details

VOLUME: 19
ISSUE: 10
Year: 2019
Page: [807 - 816]
Pages: 10
DOI: 10.2174/1568009619666190115142858
Price: $65

Article Metrics

PDF: 30
HTML: 2