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BMC Cancer
Published in: BMC Cancer 1/2011

Open Access 01-12-2011 | Research article

Molecular targeting of prostate cancer cells by a triple drug combination down-regulates integrin driven adhesion processes, delays cell cycle progression and interferes with the cdk-cyclin axis

Authors: Steffen Wedel, Lukasz Hudak, Jens-Michael Seibel, Jasmina Makarević, Eva Juengel, Igor Tsaur, Ana Waaga-Gasser, Axel Haferkamp, Roman A Blaheta

Published in: BMC Cancer | Issue 1/2011

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Abstract

Background

Single drug use has not achieved satisfactory results in the treatment of prostate cancer, despite application of increasingly widespread targeted therapeutics. In the present study, the combined impact of the mammalian target of rapamycin (mTOR)-inhibitor RAD001, the dual EGFr and VGEFr tyrosine kinase inhibitor AEE788 and the histone deacetylase (HDAC)-inhibitor valproic acid (VPA) on prostate cancer growth and adhesion in vitro was investigated.

Methods

PC-3, DU-145 and LNCaP cells were treated with RAD001, AEE788 or VPA or with a RAD-AEE-VPA combination. Tumor cell growth, cell cycle progression and cell cycle regulating proteins were then investigated by MTT-assay, flow cytometry and western blotting, respectively. Furthermore, tumor cell adhesion to vascular endothelium or to immobilized extracellular matrix proteins as well as migratory properties of the cells was evaluated, and integrin α and β subtypes were analyzed. Finally, effects of drug treatment on cell signaling pathways were determined.

Results

All drugs, separately applied, reduced tumor cell adhesion, migration and growth. A much stronger anti-cancer effect was evoked by the triple drug combination. Particularly, cdk1, 2 and 4 and cyclin B were reduced, whereas p27 was elevated. In addition, simultaneous application of RAD001, AEE788 and VPA altered the membranous, cytoplasmic and gene expression pattern of various integrin α and β subtypes, reduced integrin-linked kinase (ILK) and deactivated focal adhesion kinase (FAK). Signaling analysis revealed that EGFr and the downstream target Akt, as well as p70S6k was distinctly modified in the presence of the drug combination.

Conclusions

Simultaneous targeting of several key proteins in prostate cancer cells provides an advantage over targeting a single pathway. Since strong anti-tumor properties became evident with respect to cell growth and adhesion dynamics, the triple drug combination might provide progress in the treatment of advanced prostate cancer.
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Literature
1.
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ: Cancer statistics, 2009. CA Cancer J Clin. 2009, 59: 225-249. 10.3322/caac.20006.CrossRefPubMed
2.
Hernes E, Kyrdalen A, Kvåle R, Hem E, Klepp O, Axcrona K, Fosså SD: Initial management of prostate cancer: first year experience with the Norwegian National Prostate Cancer Registry. BJU Int. 2010, 105: 805-811. 10.1111/j.1464-410X.2009.08834.x.CrossRefPubMed
3.
Leo S, Accettura C, Lorusso V: Castration-resistant prostate cancer: targeted therapies. Chemotherapy. 2011, 57: 115-127. 10.1159/000323581.CrossRefPubMed
4.
Nørgaard M, Jensen AØ, Jacobsen JB, Cetin K, Fryzek JP, Sørensen HT: Skeletal related events, bone metastasis and survival of prostate cancer: a population based cohort study in Denmark (1999 to 2007). J Urol. 2010, 184: 162-167. 10.1016/j.juro.2010.03.034.CrossRefPubMed
5.
Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC: Natural history of progression after PSA elevation following radical prostatectomy. JAMA. 1999, 281: 1591-1597. 10.1001/jama.281.17.1591.CrossRefPubMed
6.
Petrylak DP, Tangen CM, Hussain MH, Lara PN, Jones JA, Taplin ME, Burch PA, Berry D, Moinpour C, Kohli M, Benson MC, Small EJ, Raghavan D, Crawford ED: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004, 351: 1513-1520. 10.1056/NEJMoa041318.CrossRefPubMed
7.
Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Théodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA, TAX 327 Investigators: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004, 351: 1502-1512. 10.1056/NEJMoa040720.CrossRefPubMed
8.
Morgan TM, Koreckij TD, Corey E: Targeted therapy for advanced prostate cancer: inhibition of the PI3K/Akt/mTOR pathway. Curr Cancer Drug Targets. 2009, 9: 237-249. 10.2174/156800909787580999.CrossRefPubMedPubMedCentral
9.
Liu Y, Pixley R, Fusaro M, Godoy G, Kim E, Bromberg ME, Colman RW: Cleaved high-molecular-weight kininogen and its domain 5 inhibit migration and invasion of human prostate cancer cells through the epidermal growth factor receptor pathway. Oncogene. 2009, 28: 2756-2765. 10.1038/onc.2009.132.CrossRefPubMedPubMedCentral
10.
Bianco R, Rosa R, Damiano V, Daniele G, Gelardi T, Garofalo S, Tarallo V, De Falco S, Melisi D, Benelli R, Albini A, Ryan A, Ciardiello F, Tortora G: Vascular endothelial growth factor receptor-1 contributes to resistance to anti-epidermal growth factor receptor drugs in human cancer cells. Clin Cancer Res. 2008, 14: 5069-5080. 10.1158/1078-0432.CCR-07-4905.CrossRefPubMed
11.
Zhou X, Yang XY, Popescu NC: Synergistic antineoplastic effect of DLC1 tumor suppressor protein and histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), on prostate and liver cancer cells: perspectives for therapeutics. Int J Oncol. 2010, 36: 999-1005.PubMed
12.
Blaheta RA, Michaelis M, Driever PH, Cinatl J: Evolving anticancer drug valproic acid: insights into the mechanism and clinical studies. Med Res Rev. 2005, 25: 383-397. 10.1002/med.20027.CrossRefPubMed
13.
Wedel S, Hudak L, Seibel JM, Juengel E, Oppermann E, Haferkamp A, Blaheta RA: Critical analysis of simultaneous blockage of histone deacetylase and multiple receptor tyrosine kinase in the treatment of prostate cancer. Prostate. 2010, PMID: 20954195
14.
Huamani J, Willey C, Thotala D, Niermann KJ, Reyzer M, Leavitt L, Jones C, Fleishcher A, Caprioli R, Hallahan DE, Kim DW: Differential efficacy of combined therapy with radiation and AEE788 in high and low EGFR-expressing androgen-independent prostate tumor models. Int J Radiat Oncol Biol Phys. 2008, 71: 237-246. 10.1016/j.ijrobp.2007.12.049.CrossRefPubMedPubMedCentral
15.
Dhupkar P, Dowling M, Cengel K, Chen B: Effects of anti-EGFR antibody cetuximab on androgen-independent prostate cancer cells. Anticancer Res. 2010, 30: 1905-1910.PubMed
16.
Wu L, Birle DC, Tannock IF: Effects of the mammalian target of rapamycin inhibitor CCI-779 used alone or with chemotherapy on human prostate cancer cells and xenografts. Cancer Res. 2005, 65: 2825-2831. 10.1158/0008-5472.CAN-04-3137.CrossRefPubMed
17.
Björkman M, Iljin K, Halonen P, Sara H, Kaivanto E, Nees M, Kallioniemi OP: Defining the molecular action of HDAC inhibitors and synergism with androgen deprivation in ERG-positive prostate cancer. Int J Cancer. 2008, 123: 2774-2781. 10.1002/ijc.23885.CrossRefPubMed
18.
Dai B, Kong YY, Ye DW, Ma CG, Zhou X, Yao XD: Activation of the mammalian target of rapamycin signalling pathway in prostate cancer and its association with patient clinicopathological characteristics. BJU Int. 2009, 104: 1009-1016. 10.1111/j.1464-410X.2009.08538.x.CrossRefPubMed
19.
Ohlmann CH, Markert E, Gerharz M, Dienes HP, Stöckle M, Engelmann U, Heidenreich A: Improving the efficacy of targeted trials by multiple-marker analysis in castration-resistant prostate cancer. Urol Oncol. 2009, PubMed PMID: 19942459
20.
Weichert W, Röske A, Gekeler V, Beckers T, Stephan C, Jung K, Fritzsche FR, Niesporek S, Denkert C, Dietel M, Kristiansen G: Histone deacetylases 1, 2 and 3 are highly expressed in prostate cancer and HDAC2 expression is associated with shorter PSA relapse time after radical prostatectomy. Br J Cancer. 2008, 98: 604-610. 10.1038/sj.bjc.6604199.CrossRefPubMedPubMedCentral
21.
Raina K, Rajamanickam S, Deep G, Singh M, Agarwal R, Agarwal C: Chemopreventive effects of oral gallic acid feeding on tumor growth and progression in TRAMP mice. Mol Cancer Ther. 2008, 7: 1258-1267. 10.1158/1535-7163.MCT-07-2220.CrossRefPubMed
22.
Tyagi A, Agarwal C, Agarwal R: The cancer preventive flavonoid silibinin causes hypophosphorylation of Rb/p107 and Rb2/p130 via modulation of cell cycle regulators in human prostate carcinoma DU145 cells. Cell Cycle. 2002, 1: 137-142.CrossRefPubMed
23.
Palozza P, Colangelo M, Simone R, Catalano A, Boninsegna A, Lanza P, Monego G, Ranelletti FO: Lycopene induces cell growth inhibition by altering mevalonate pathway and Ras signaling in cancer cell lines. Carcinogenesis. 2010, 31: 1813-1821. 10.1093/carcin/bgq157.CrossRefPubMed
24.
Chan QK, Lam HM, Ng CF, Lee AY, Chan ES, Ng HK, Ho SM, Lau KM: Activation of GPR30 inhibits the growth of prostate cancer cells through sustained activation of Erk1/2, c-jun/c-fos-dependent upregulation of p21, and induction of G(2) cell-cycle arrest. Cell Death Differ. 2010, 17: 1511-1523. 10.1038/cdd.2010.20.CrossRefPubMedPubMedCentral
25.
Wang Z, Lee HJ, Chai Y, Hu H, Wang L, Zhang Y, Jiang C, Lü J: Persistent p21Cip1 induction mediates G(1) cell cycle arrest by methylseleninic acid in DU145 prostate cancer cells. Curr Cancer Drug Targets. 2010, 10: 307-318. 10.2174/156800910791190238.CrossRefPubMed
26.
Li X, Chen BD: Histone Deacetylase Inhibitor M344 Inhibits Cell Proliferation and Induces Apoptosis in Human THP-1 Leukemia Cells. Am J Biomed Sci. 2009, 1: 352-363.CrossRefPubMedPubMedCentral
27.
Yu X, Guo ZS, Marcu MG, Neckers L, Nguyen DM, Chen GA, Schrump DS: Modulation of p53, ErbB1, ErbB2, and Raf-1 expression in lung cancer cells by depsipeptide FR901228. J Natl Cancer Inst. 2002, 94: 504-513.CrossRefPubMed
28.
Im JY, Park H, Kang KW, Choi WS, Kim HS: Modulation of cell cycles and apoptosis by apicidin in estrogen receptor (ER)-positive and-negative human breast cancer cells. Chem Biol Interact. 2008, 172: 235-244. 10.1016/j.cbi.2008.01.007.CrossRefPubMed
29.
Qu W, Kang YD, Zhou MS, Fu LL, Hua ZH, Wang LM: Experimental study on inhibitory effects of histone deacetylase inhibitor MS-275 and TSA on bladder cancer cells. Urol Oncol. 2009, 28: 648-654.CrossRefPubMed
30.
Juengel E, Engler J, Natsheh I, Jones J, Mickuckyte A, Hudak L, Jonas D, Blaheta RA: Combining the receptor tyrosine kinase inhibitor AEE788 and the mammalian target of rapamycin (mTOR) inhibitor RAD001 strongly inhibits adhesion and growth of renal cell carcinoma cells. BMC Cancer. 2009, 9: 161-10.1186/1471-2407-9-161.CrossRefPubMedPubMedCentral
31.
Sarkar S, Mazumdar A, Dash R, Sarkar D, Fisher PB, Mandal M: ZD6474, a dual tyrosine kinase inhibitor of EGFR and VEGFR-2, inhibits MAPK/ERK and AKT/PI3-K and induces apoptosis in breast cancer cells. Cancer Biol Ther. 2010, 9: 592-603. 10.4161/cbt.9.8.11103.CrossRefPubMed
32.
Yang F, Brown C, Buettner R, Hedvat M, Starr R, Scuto A, Schroeder A, Jensen M, Jove R: Sorafenib induces growth arrest and apoptosis of human glioblastoma cells through the dephosphorylation of signal transducers and activators of transcription 3. Mol Cancer Ther. 2010, 9: 953-962. 10.1158/1535-7163.MCT-09-0947.CrossRefPubMedPubMedCentral
33.
Yang F, Jove V, Xin H, Hedvat M, Van Meter TE, Yu H: Sunitinib induces apoptosis and growth arrest of medulloblastoma tumor cells by inhibiting STAT3 and AKT signaling pathways. Mol Cancer Res. 2010, 8: 35-45. 10.1158/1541-7786.MCR-09-0220.CrossRefPubMedPubMedCentral
34.
Takezawa K, Okamoto I, Yonesaka K, Hatashita E, Yamada Y, Fukuoka M, Nakagawa K: Sorafenib inhibits non-small cell lung cancer cell growth by targeting B-RAF in KRAS wild-type cells and C-RAF in KRAS mutant cells. Cancer Res. 2009, 69: 6515-6521. 10.1158/0008-5472.CAN-09-1076.CrossRefPubMed
35.
Degeorges A, Hoffschir F, Cussenot O, Gauville C, Le Duc A, Dutrillaux B, Calvo F: Recurrent cytogenetic alterations of prostate carcinoma and amplification of c-myc or epidermal growth factor receptor in subclones of immortalized PNT1 human prostate epithelial cell line. Int J Cancer. 1995, 62: 724-731. 10.1002/ijc.2910620613.CrossRefPubMed
36.
Jackson-Cook C, Zou Y, Turner K, Astbury C, Ware J: A novel tumorigenic human prostate epithelial cell line (M2205): molecular cytogenetic characterization demonstrates C-MYC amplification and jumping translocations. Cancer Genet Cytogenet. 2003, 141: 56-64. 10.1016/S0165-4608(02)00665-9.CrossRefPubMed
37.
Nagakawa O, Akashi T, Hayakawa Y, Junicho A, Koizumi K, Fujiuchi Y, Furuya Y, Matsuda T, Fuse H, Saiki I: Differential expression of integrin subunits in DU-145/AR prostate cancer cells. Oncol Rep. 2004, 12: 837-841.PubMed
38.
Shen X, Falzon M: Parathyroid hormone-related protein upregulates integrin expression via an intracrine pathway in PC-3 prostate cancer cells. Regul Pept. 2003, 113: 17-29. 10.1016/S0167-0115(02)00293-8.CrossRefPubMed
39.
40.
Dedhar S, Saulnier R, Nagle R, Overall CM: Specific alterations in the expression of alpha 3 beta 1 and alpha 6 beta 4 integrins in highly invasive and metastatic variants of human prostate carcinoma cells selected by in vitro invasion through reconstituted basement membrane. Clin Exp Metastasis. 1993, 11: 391-400. 10.1007/BF00132982.CrossRefPubMed
41.
Goel HL, Moro L, King M, Teider N, Centrella M, McCarthy TL, Holgado-Madruga M, Wong AJ, Marra E, Languino LR: Beta1 integrins modulate cell adhesion by regulating insulin-like growth factor-II levels in the microenvironment. Cancer Res. 2006, 66: 331-342. 10.1158/0008-5472.CAN-05-2588.CrossRefPubMed
42.
Goel HL, Underwood JM, Nickerson JA, Hsieh CC, Languino LR: Beta1 integrins mediate cell proliferation in three-dimensional cultures by regulating expression of the sonic hedgehog effector protein, GLI1. J Cell Physiol. 2010, 224: 210-217.PubMedPubMedCentral
43.
Caswell PT, Norman JC: Integrin trafficking and the control of cell migration. Traffic. 2006, 7: 14-21. 10.1111/j.1600-0854.2005.00362.x.CrossRefPubMed
44.
Kobayashi T, Shimizu Y, Terada N, Yamasaki T, Nakamura E, Toda Y, Nishiyama H, Kamoto T, Ogawa O, Inoue T: Regulation of androgen receptor transactivity and mTOR-S6 kinase pathway by Rheb in prostate cancer cell proliferation. Prostate. 2010, 70: 866-874.PubMed
45.
Roca H, Varsos Z, Pienta KJ: CCL2 protects prostate cancer PC3 cells from autophagic death via phosphatidylinositol 3-kinase/AKT-dependent surviving up-regulation. J Biol Chem. 2008, 283: 25057-25073. 10.1074/jbc.M801073200.CrossRefPubMedPubMedCentral
46.
Sun SY, Rosenberg LM, Wang X, Zhou Z, Yue P, Fu H, Khuri FR: Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res. 2005, 65: 7052-7058. 10.1158/0008-5472.CAN-05-0917.CrossRefPubMed
47.
Yee KW, Zeng Z, Konopleva M, Verstovsek S, Ravandi F, Ferrajoli A, Thomas D, Wierda W, Apostolidou E, Albitar M, O'Brien S, Andreeff M, Giles FJ: Phase I/II study of the mammalian target of rapamycin inhibitor everolimus (RAD001) in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res. 2006, 12: 5165-5173. 10.1158/1078-0432.CCR-06-0764.CrossRefPubMed
48.
Thompson TC: Turning reciprocal feedback regulation into combination therapy. Cancer Cell. 2011, 19: 697-699. 10.1016/j.ccr.2011.05.022.CrossRefPubMed
49.
Kinkade CW, Castillo-Martin M, Puzio-Kuter A, Yan J, Foster TH, Gao H, Sun Y, Ouyang X, Gerald WL, Cordon-Cardo C, Abate-Shen C: Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model. J Clin Invest. 2008, 118: 3051-3064.PubMedPubMedCentral
50.
Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, Egia A, Sasaki AT, Thomas G, Kozma SC, Papa A, Nardella C, Cantley LC, Baselga J, Pandolfi PP: Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest. 2008, 118: 3065-3074.PubMedPubMedCentral
51.
Galsky MD, Vogelzang NJ: Docetaxel-based combination therapy for castration-resistant prostate cancer. Ann Oncol. 2010, 21: 2135-2144. 10.1093/annonc/mdq050.CrossRefPubMed
Metadata
Title
Molecular targeting of prostate cancer cells by a triple drug combination down-regulates integrin driven adhesion processes, delays cell cycle progression and interferes with the cdk-cyclin axis
Authors
Steffen Wedel
Lukasz Hudak
Jens-Michael Seibel
Jasmina Makarević
Eva Juengel
Igor Tsaur
Ana Waaga-Gasser
Axel Haferkamp
Roman A Blaheta
Publication date
01-12-2011
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2011
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-11-375

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