The microtubule stabilizer patupilone counteracts ionizing radiation-induced matrix metalloproteinase activity and tumor cell invasion

Radiation Oncology

Martin Pruschy²  Anne-Laure Millard¹  Matthias Eggel³  Angela Broggini-Tenzer²  Polina Furmanova-Hollenstein² 

[1] Institute for Cell Biology, University Berne, Berne, Switzerland;Laboratory for Molecular Radiobiology, University Hospital Zurich, Rämistrasse 100, Zurich, 8091, Switzerland;Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland

关键词: Patupilone;    Microtubule stabilizing agent;    Ionizing radiation;    Tissue inhibitor of metalloproteinases;    Matrix metalloproteinase;   

Others  :  1154056
DOI  :  10.1186/1748-717X-8-105

 received in 2012-11-06, accepted in 2013-04-23,  发布年份 2013

【 摘 要 】

Background

Ionizing radiation (IR) in combination with microtubule stabilizing agents (MSA) is a promising combined treatment modality. Supra-additive treatment responses might result from direct tumor cell killing and cooperative indirect, tumor cell-mediated effects on the tumor microenvironment. Here we investigated deregulation of matrix metalloproteinase (MMP) activity, as an important component of the tumor microenvironment, by the combined treatment modality of IR with the clinically relevant MSA patupilone.

Methods

Expression, secretion and activity of MMPs and related tissue inhibitors of metalloproteinases (TIMPs) were determined in cell extracts and conditioned media derived from human fibrosarcoma HT1080 and human glioblastoma U251 tumor cells in response to treatment with IR and the MSA patupilone. Treatment-dependent changes of the invasive capacities of these tumor cell lines were analysed using a Transwell invasion assay. Control experiments were performed using TIMP-directed siRNA and TIMP-directed inhibitory antibodies.

Results

Enzymatic activity of secreted MMPs was determined after treatment with patupilone and irradiation in the human fibrosarcoma HT1080 and the human glioblastoma U251 tumor cell line. IR enhanced the activity of secreted MMPs up to 2-fold and cellular pretreatment with low dose patupilone (0.05-0.2 nM) counteracted specifically the IR-induced MMP activity. The cell invasive capacity of HT1080 and U251 cells was increased after irradiation with 2 Gy by 30% and 50%, respectively, and patupilone treatment completely abrogated IR-induced cell invasion. Patupilone did not alter the level of MMP expression, but interestingly, the protein level of secreted TIMP-1 and TIMP-2 was lower after combined treatment than after irradiation treatment alone. Furthermore, siRNA depletion of TIMP-1 or TIMP-2 prevented IR-mediated induction of MMP activity and cell invasion.

Conclusions

These results indicate that patupilone counteracts an IR-induced MMP activation process by the reduction of secreted TIMP-1 and TIMP-2 proteins, which are required for activation of MMPs. Since IR-induced MMP activity could contribute to tumor progression, treatment combination of IR with patupilone might be of great clinical benefit for tumor therapy.

【 授权许可】

   
2013 Furmanova-Hollenstein et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Bonomi P, Kim K, Fairclough D, Cella D, Kugler J, Rowinsky E, Jiroutek M, Johnson D: Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial. J Clin Oncol 2000, 18:623-631.
• [2]Jones SE, Erban J, Overmoyer B, Budd GT, Hutchins L, Lower E, Laufman L, Sundaram S, Urba WJ, Pritchard KI, et al.: Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol 2005, 23:5542-5551.
• [3]Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Theodore C, James ND, Turesson I, et al.: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004, 351:1502-1512.
• [4]Bollag DM, McQueney PA, Zhu J, Hensens O, Koupal L, Liesch J, Goetz M, Lazarides E, Woods CM: Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action. Cancer Res 1995, 55:2325-2333.
• [5]Buey RM, Diaz JF, Andreu JM, O’Brate A, Giannakakou P, Nicolaou KC, Sasmal PK, Ritzen A, Namoto K: Interaction of epothilone analogs with the paclitaxel binding site: relationship between binding affinity, microtubule stabilization, and cytotoxicity. Chem Biol 2004, 11:225-236.
• [6]Risinger AL, Giles FJ, Mooberry SL: Microtubule dynamics as a target in oncology. Cancer Treat Rev 2009, 35:255-261.
• [7]Cigler T, Vahdat L: Integrating epothilones into the treatment of patients with metastatic breast cancer: clinical perspectives on incorporating recent data in the practice setting. Clin Breast Cancer 2008, 8(Suppl 4):S166-S170.
• [8]Fogh S, Machtay M, Werner-Wasik M, Curran WJ Jr, Bonanni R, Axelrod R, Andrews D, Dicker AP: Phase I trial using patupilone (epothilone B) and concurrent radiotherapy for central nervous system malignancies. Int J Radiat Oncol Biol Phys 2010, 77:1009-1016.
• [9]Hussain A, DiPaola RS, Baron AD, Higano CS, Tchekmedyian NS, Johri AR: Phase II trial of weekly patupilone in patients with castration-resistant prostate cancer. Ann Oncol 2009, 20:492-497.
• [10]Rubin EH, Rothermel J, Tesfaye F, Chen T, Hubert M, Ho YY, Hsu CH, Oza AM: Phase I dose-finding study of weekly single-agent patupilone in patients with advanced solid tumors. J Clin Oncol 2005, 23:9120-9129.
• [11]Oehler C, Frei K, Rushing EJ, McSheehy PM, Weber D, Allegrini PR, Weniger D, Lutolf UM, Knuth A, Yonekawa Y, et al.: Patupilone (epothilone B) for recurrent glioblastoma: clinical outcome and translational analysis of a single-institution phase I/II trial. Oncology 2012, 83:1-9.
• [12]Alvarez RH, Valero V, Hortobagyi GN: Ixabepilone for the treatment of breast cancer. Ann Med 2011, 43:477-486.
• [13]Kaklamani VG, Xu BH, Gomez HL: Global experience with ixabepilone in breast cancer. Expert Rev Anticancer Ther 2011, 11:683-692.
• [14]Bley CR, Jochum W, Orlowski K, Furmanova P, Vuong V, McSheehy PM, Pruschy M: Role of the microenvironment for radiosensitization by patupilone. Clin Cancer Res 2009, 15:1335-1342.
• [15]Hofstetter B, Vuong V, Broggini-Tenzer A, Bodis S, Ciernik IF, Fabbro D, Wartmann M, Folkers G, Pruschy M: Patupilone acts as radiosensitizing agent in multidrug-resistant cancer cells in vitro and in vivo. Clin Cancer Res 2005, 11:1588-1596.
• [16]Oehler C, von Bueren AO, Furmanova P, Broggini-Tenzer A, Orlowski K, Rutkowski S, Frei K, Grotzer MA, Pruschy M: The microtubule stabilizer patupilone (epothilone B) is a potent radiosensitizer in medulloblastoma cells. Neuro Oncol 2011, 13:1000-1010.
• [17]Bijman MN, van Nieuw Amerongen GP, Laurens N, van Hinsbergh VW, Boven E: Microtubule-targeting agents inhibit angiogenesis at subtoxic concentrations, a process associated with inhibition of Rac1 and Cdc42 activity and changes in the endothelial cytoskeleton. Mol Cancer Ther 2006, 5:2348-2357.
• [18]Ferretti S, Allegrini PR, O’Reilly T, Schnell C, Stumm M, Wartmann M, Wood J, McSheehy PM: Patupilone induced vascular disruption in orthotopic rodent tumor models detected by magnetic resonance imaging and interstitial fluid pressure. Clin Cancer Res 2005, 11:7773-7784.
• [19]Rohrer Bley C, Orlowski K, Furmanova P, McSheehy PM, Pruschy M: Regulation of VEGF-expression by patupilone and ionizing radiation in lung adenocarcinoma cells. Lung Cancer 2011, 73:294-301.
• [20]Sbai O, Ferhat L, Bernard A, Gueye Y, Ould-Yahoui A, Thiolloy S, Charrat E, Charton G, Tremblay E, Risso JJ, et al.: Vesicular trafficking and secretion of matrix metalloproteinases-2, -9 and tissue inhibitor of metalloproteinases-1 in neuronal cells. Mol Cell Neurosci 2008, 39:549-568.
• [21]Schnaeker EM, Ossig R, Ludwig T, Dreier R, Oberleithner H, Wilhelmi M, Schneider SW: Microtubule-dependent matrix metalloproteinase-2/matrix metalloproteinase-9 exocytosis: prerequisite in human melanoma cell invasion. Cancer Res 2004, 64:8924-8931.
• [22]Stearns ME, Wang M: Taxol blocks processes essential for prostate tumor cell (PC-3 ML) invasion and metastases. Cancer Res 1992, 52:3776-3781.
• [23]Egeblad M, Werb Z: New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2002, 2:161-174.
• [24]Kessenbrock K, Plaks V, Werb Z: Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 2010, 141:52-67.
• [25]Cruz-Munoz W, Khokha R: The role of tissue inhibitors of metalloproteinases in tumorigenesis and metastasis. Crit Rev Clin Lab Sci 2008, 45:291-338.
• [26]Lichte A, Kolkenbrock H, Tschesche H: The recombinant catalytic domain of membrane-type matrix metalloproteinase-1 (MT1-MMP) induces activation of progelatinase A and progelatinase A complexed with TIMP-2. FEBS Lett 1996, 397:277-282.
• [27]Lizarraga F, Maldonado V, Melendez-Zajgla J: Tissue inhibitor of metalloproteinases-2 growth-stimulatory activity is mediated by nuclear factor-kappa B in A549 lung epithelial cells. Int J Biochem Cell Biol 2004, 36:1655-1663.
• [28]Guedez L, Courtemanch L, Stetler-Stevenson M: Tissue inhibitor of metalloproteinase (TIMP)-1 induces differentiation and an antiapoptotic phenotype in germinal center B cells. Blood 1998, 92:1342-1349.
• [29]Lambert E, Bridoux L, Devy J, Dasse E, Sowa ML, Duca L, Hornebeck W, Martiny L, Petitfrere-Charpentier E: TIMP-1 binding to proMMP-9/CD44 complex localized at the cell surface promotes erythroid cell survival. Int J Biochem Cell Biol 2009, 41:1102-1115.
• [30]Agemy L, Harmelin A, Waks T, Leibovitch I, Rabin T, Pfeffer MR, Eshhar Z: Irradiation enhances the metastatic potential of prostatic small cell carcinoma xenografts. Prostate 2008, 68:530-539.
• [31]Camphausen K, Moses MA, Beecken WD, Khan MK, Folkman J, O’Reilly MS: Radiation therapy to a primary tumor accelerates metastatic growth in mice. Cancer Res 2001, 61:2207-2211.
• [32]Susskind H, Hymowitz MH, Lau YH, Atkins HL, Hurewitz AN, Valentine ES, Meek AG, Zucker S: Increased plasma levels of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in lung and breast cancer are altered during chest radiotherapy. Int J Radiat Oncol Biol Phys 2003, 56:1161-1169.
• [33]Partridge JJ, Madsen MA, Ardi VC, Papagiannakopoulos T, Kupriyanova TA, Quigley JP, Deryugina EI: Functional analysis of matrix metalloproteinases and tissue inhibitors of metalloproteinases differentially expressed by variants of human HT-1080 fibrosarcoma exhibiting high and low levels of intravasation and metastasis. J Biol Chem 2007, 282:35964-35977.
• [34]Yokoyama Y, Dhanabal M, Griffioen AW, Sukhatme VP, Ramakrishnan S: Synergy between angiostatin and endostatin: inhibition of ovarian cancer growth. Cancer Res 2000, 60:2190-2196.
• [35]Broggini-Tenzer A, Hollenstein A, Pianowski Z, Wampfler A, Furmanova P, Winssinger N, Pruschy M: Substrate screening identifies a novel target sequence for the proteasomal activity regulated by ionizing radiation. Proteomics 2010, 10:304-314.
• [36]Domeij H, Modeer T, Yucel-Lindberg T: Matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 production in human gingival fibroblasts: the role of protein kinase C. J Periodontal Res 2004, 39:308-314.
• [37]Park MJ, Park IC, Hur JH, Rhee CH, Choe TB, Yi DH, Hong SI, Lee SH: Protein kinase C activation by phorbol ester increases in vitro invasion through regulation of matrix metalloproteinases/tissue inhibitors of metalloproteinases system in D54 human glioblastoma cells. Neurosci Lett 2000, 290:201-204.
• [38]Chakraborti S, Mandal M, Das S, Mandal A, Chakraborti T: Regulation of matrix metalloproteinases: an overview. Mol Cell Biochem 2003, 253:269-285.
• [39]Galazka G, Windsor LJ, Birkedal-Hansen H, Engler JA: APMA (4-aminophenylmercuric acetate) activation of stromelysin-1 involves protein interactions in addition to those with cysteine-75 in the propeptide. Biochemistry 1996, 35:11221-11227.
• [40]Kaliski A, Maggiorella L, Cengel KA, Mathe D, Rouffiac V, Opolon P, Lassau N, Bourhis J, Deutsch E: Angiogenesis and tumor growth inhibition by a matrix metalloproteinase inhibitor targeting radiation-induced invasion. Mol Cancer Ther 2005, 4:1717-1728.
• [41]O’Reilly T, McSheehy PM, Wenger F, Hattenberger M, Muller M, Vaxelaire J, Altmann KH, Wartmann M: Patupilone (epothilone B, EPO906) inhibits growth and metastasis of experimental prostate tumors in vivo. Prostate 2005, 65:231-240.
• [42]O’Reilly T, Wartmann M, Brueggen J, Allegrini PR, Floersheimer A, Maira M, McSheehy PM: Pharmacokinetic profile of the microtubule stabilizer patupilone in tumor-bearing rodents and comparison of anti-cancer activity with other MTS in vitro and in vivo. Cancer Chemother Pharmacol 2008, 62:1045-1054.
• [43]Lee SH, Son SM, Son DJ, Kim SM, Kim TJ, Song S, Moon DC, Lee HW, Ryu JC, Yoon DY, Hong JT: Epothilones induce human colon cancer SW620 cell apoptosis via the tubulin polymerization independent activation of the nuclear factor-kappaB/IkappaB kinase signal pathway. Mol Cancer Ther 2007, 6:2786-2797.
• [44]Borghaei RC, Gorski G, Javadi M: NF-kappaB and ZBP-89 regulate MMP-3 expression via a polymorphic site in the promoter. Biochem Biophys Res Commun 2009, 382:269-273.
• [45]Cheng JC, Chou CH, Kuo ML, Hsieh CY: Radiation-enhanced hepatocellular carcinoma cell invasion with MMP-9 expression through PI3K/Akt/NF-kappaB signal transduction pathway. Oncogene 2006, 25:7009-7018.
• [46]Lee SK, Kim JM, Lee MY, Son KH, Yeom YI, Kim CH, Shin Y, Koh JS, Han DC, Kwon BM: Confirmation of a linkage between H-Ras and MMP-13 expression as well as MMP-9 by chemical genomic approach. Int J Cancer 2006, 118:2172-2181.
• [47]Park CM, Park MJ, Kwak HJ, Lee HC, Kim MS, Lee SH, Park IC, Rhee CH, Hong SI: Ionizing radiation enhances matrix metalloproteinase-2 secretion and invasion of glioma cells through Src/epidermal growth factor receptor-mediated p38/Akt and phosphatidylinositol 3-kinase/Akt signaling pathways. Cancer Res 2006, 66:8511-8519.
• [48]Butler GS, Hutton M, Wattam BA, Williamson RA, Knauper V, Willenbrock F, Murphy G: The specificity of TIMP-2 for matrix metalloproteinases can be modified by single amino acid mutations. J Biol Chem 1999, 274:20391-20396.
• [49]Curry TE Jr, Osteen KG: The matrix metalloproteinase system: changes, regulation, and impact throughout the ovarian and uterine reproductive cycle. Endocr Rev 2003, 24:428-465.
• [50]Strongin AY, Collier I, Bannikov G, Marmer BL, Grant GA, Goldberg GI: Mechanism of cell surface activation of 72-kDa type IV collagenase. Isolation of the activated form of the membrane metalloprotease. J Biol Chem 1995, 270:5331-5338.
• [51]Brew K, Dinakarpandian D, Nagase H: Tissue inhibitors of metalloproteinases: evolution, structure and function. Biochim Biophys Acta 2000, 1477:267-283.
• [52]Stupp R, Hegi ME, Gilbert MR, Chakravarti A: Chemoradiotherapy in malignant glioma: standard of care and future directions. J Clin Oncol 2007, 25:4127-4136.
• [53]Forsyth PA, Wong H, Laing TD, Rewcastle NB, Morris DG, Muzik H, Leco KJ, Johnston RN, Brasher PM, Sutherland G, Edwards DR: Gelatinase-A (MMP-2), gelatinase-B (MMP-9) and membrane type matrix metalloproteinase-1 (MT1-MMP) are involved in different aspects of the pathophysiology of malignant gliomas. Br J Cancer 1999, 79:1828-1835.
• [54]Wild-Bode C, Weller M, Rimner A, Dichgans J, Wick W: Sublethal irradiation promotes migration and invasiveness of glioma cells: implications for radiotherapy of human glioblastoma. Cancer Res 2001, 61:2744-2750.