This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Peng, D. Articles by Mendelsohn, J. Search for Related Content PubMed PubMed Citation Articles by Peng, D. Articles by Mendelsohn, J.

Anti-Epidermal Growth Factor Receptor Monoclonal Antibody 225 Up-Regulates p27^KIP1 and Induces G₁ Arrest in Prostatic Cancer Cell Line DU145¹

Laboratory of Receptor Biology, Program in Molecular Pharmacology and Therapeutics [D. P., Z. F., Y. L., T. D., J. M.], Genitourinary Oncology Service [H. S.], and Department of Medicine [Z. F., H. S., J. M.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021; and Department of Medicine, Cornell University Medical College, New York, NY 10021 [H. S., J. M.]

Autocrine production of transforming growth factor and overexpression of the epidermal growth factor receptor (EGFR) may contribute to androgen-independent prostatic cancer growth at both primary and metastatic sites. Previously, we showed that human EGFR-blocking monoclonal antibody mAb225 inhibited the growth of DU145 human prostatic cancer cells. Here we explore the hypothesis that mAb225 may act by interfering with cell cycle traversal in these cells. Treatment with mAb225 induced G₁ arrest, which was accompanied by a marked decrease in CDK2-, cyclin A-, and cyclin E-associated histone H1 kinase activities, and a sustained increase in cell cycle inhibitor p27^KIP1. The increased p27^KIP1 levels were attributable to elevation of both transcription and translation. CDK2 associated with p27^KIP1 was increased in mAb225-treated DU145 cells. The retinoblastoma-related protein p130 remained hypophosphorylated in these retinoblastoma-negative cells. These studies demonstrate that the antiproliferative effect of EGFR blockade in DU145 cells may be mediated by up-regulation of p27^KIP1 at both the mRNA and protein levels.

¹ This study was supported in part by grants from CaPCURE and the Pepsi Co. Foundation. J. M. was supported by NIH Grants CA42060 and CA37641. H. S. was supported by NIH Grant CA05826.

² The first two authors contributed equally to this study.

³ To whom requests for reprints should be addressed, at the University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 91, Houston, TX 77030.

Received 5/23/96. Accepted 7/15/96.

This article has been cited by other articles:

				H.-J. Liao and G. Carpenter Cetuximab/C225-Induced Intracellular Trafficking of Epidermal Growth Factor Receptor Cancer Res., August 1, 2009; 69(15): 6179 - 6183. [Abstract] [Full Text] [PDF]

				B. Corkery, J. Crown, M. Clynes, and N. O'Donovan Epidermal growth factor receptor as a potential therapeutic target in triple-negative breast cancer Ann. Onc., May 1, 2009; 20(5): 862 - 867. [Abstract] [Full Text] [PDF]

				E. M. Levy, G. Sycz, J. M. Arriaga, M. M. Barrio, E. M. von Euw, S. B. Morales, M. Gonzalez, J. Mordoh, and M. Bianchini Cetuximab-mediated cellular cytotoxicity is inhibited by HLA-E membrane expression in colon cancer cells Innate Immunity, April 1, 2009; 15(2): 91 - 100. [Abstract] [PDF]

				S. Staal, M. J. O'Connell, and C. J. Allegra The Marriage of Growth Factor Inhibitors and Chemotherapy: Bliss or Bust? J. Clin. Oncol., April 1, 2009; 27(10): 1545 - 1548. [Full Text] [PDF]

				C. Bengala, S. Bettelli, F. Bertolini, S. Salvi, S. Chiara, C. Sonaglio, L. Losi, N. Bigiani, G. Sartori, C. Dealis, et al. Epidermal growth factor receptor gene copy number, K-ras mutation and pathological response to preoperative cetuximab, 5-FU and radiation therapy in locally advanced rectal cancer Ann. Onc., March 1, 2009; 20(3): 469 - 474. [Abstract] [Full Text] [PDF]

				M. Peipp, T. Schneider-Merck, M. Dechant, T. Beyer, J. J. Lammerts van Bueren, W. K. Bleeker, P. W. H. I. Parren, J. G. J. van de Winkel, and T. Valerius Tumor Cell Killing Mechanisms of Epidermal Growth Factor Receptor (EGFR) Antibodies Are Not Affected by Lung Cancer-Associated EGFR Kinase Mutations J. Immunol., March 15, 2008; 180(6): 4338 - 4345. [Abstract] [Full Text] [PDF]

				P. M. Harari, G. W. Allen, and J. A. Bonner Biology of Interactions: Antiepidermal Growth Factor Receptor Agents J. Clin. Oncol., September 10, 2007; 25(26): 4057 - 4065. [Abstract] [Full Text] [PDF]

				H.-J. Lenz, E. Van Cutsem, S. Khambata-Ford, R. J. Mayer, P. Gold, P. Stella, B. Mirtsching, A. L. Cohn, A. W. Pippas, N. Azarnia, et al. Multicenter Phase II and Translational Study of Cetuximab in Metastatic Colorectal Carcinoma Refractory to Irinotecan, Oxaliplatin, and Fluoropyrimidines J. Clin. Oncol., October 20, 2006; 24(30): 4914 - 4921. [Abstract] [Full Text] [PDF]

				M. S. Pino, M. Shrader, C. H. Baker, F. Cognetti, H. Q. Xiong, J. L. Abbruzzese, and D. J. McConkey Transforming Growth Factor {alpha} Expression Drives Constitutive Epidermal Growth Factor Receptor Pathway Activation and Sensitivity to Gefitinib (Iressa) in Human Pancreatic Cancer Cell Lines. Cancer Res., April 1, 2006; 66(7): 3802 - 3812. [Abstract] [Full Text] [PDF]

				S. Kim, C. N. Prichard, M. N. Younes, Y. D. Yazici, S. A. Jasser, B. N. Bekele, and J. N. Myers Cetuximab and Irinotecan Interact Synergistically to Inhibit the Growth of Orthotopic Anaplastic Thyroid Carcinoma Xenografts in Nude Mice Clin. Cancer Res., January 15, 2006; 12(2): 600 - 607. [Abstract] [Full Text] [PDF]

				U. Reusch, M. Sundaram, P. A. Davol, S. D. Olson, J. B. Davis, K. Demel, J. Nissim, R. Rathore, P. Y. Liu, and L. G. Lum Anti-CD3 x Anti-Epidermal Growth Factor Receptor (EGFR) Bispecific Antibody Redirects T-Cell Cytolytic Activity to EGFR-Positive Cancers In vitro and in an Animal Model Clin. Cancer Res., January 1, 2006; 12(1): 183 - 190. [Abstract] [Full Text] [PDF]

				F. Robert, G. Blumenschein, R. S. Herbst, F. V. Fossella, J. Tseng, M. N. Saleh, and M. Needle Phase I/IIa Study of Cetuximab With Gemcitabine Plus Carboplatin in Patients With Chemotherapy-Naive Advanced Non-Small-Cell Lung Cancer J. Clin. Oncol., December 20, 2005; 23(36): 9089 - 9096. [Abstract] [Full Text] [PDF]

				S. K. Mohsin, H. L. Weiss, M. C. Gutierrez, G. C. Chamness, R. Schiff, M. P. DiGiovanna, C.-X. Wang, S. G. Hilsenbeck, C. K. Osborne, D. C. Allred, et al. Neoadjuvant Trastuzumab Induces Apoptosis in Primary Breast Cancers J. Clin. Oncol., April 10, 2005; 23(11): 2460 - 2468. [Abstract] [Full Text] [PDF]

				C. D. Woodworth, E. Michael, D. Marker, S. Allen, L. Smith, and M. Nees Inhibition of the epidermal growth factor receptor increases expression of genes that stimulate inflammation, apoptosis, and cell attachment Mol. Cancer Ther., April 1, 2005; 4(4): 650 - 658. [Abstract] [Full Text] [PDF]

				S. Dubey and J. H. Schiller Three Emerging New Drugs for NSCLC: Pemetrexed, Bortezomib, and Cetuximab Oncologist, April 1, 2005; 10(4): 282 - 291. [Abstract] [Full Text] [PDF]

				P. Matar, F. Rojo, R. Cassia, G. Moreno-Bueno, S. Di Cosimo, J. Tabernero, M. Guzman, S. Rodriguez, J. Arribas, J. Palacios, et al. Combined Epidermal Growth Factor Receptor Targeting with the Tyrosine Kinase Inhibitor Gefitinib (ZD1839) and the Monoclonal Antibody Cetuximab (IMC-C225): Superiority Over Single-Agent Receptor Targeting Clin. Cancer Res., October 1, 2004; 10(19): 6487 - 6501. [Abstract] [Full Text] [PDF]

				L. B. Saltz, N. J. Meropol, P. J. Loehrer Sr, M. N. Needle, J. Kopit, and R. J. Mayer Phase II Trial of Cetuximab in Patients With Refractory Colorectal Cancer That Expresses the Epidermal Growth Factor Receptor J. Clin. Oncol., April 1, 2004; 22(7): 1201 - 1208. [Abstract] [Full Text] [PDF]

				J. Mendelsohn and J. Baselga Status of Epidermal Growth Factor Receptor Antagonists in the Biology and Treatment of Cancer J. Clin. Oncol., July 15, 2003; 21(14): 2787 - 2799. [Abstract] [Full Text] [PDF]

				V. Grunwald and M. Hidalgo Developing Inhibitors of the Epidermal Growth Factor Receptor for Cancer Treatment J Natl Cancer Inst, June 18, 2003; 95(12): 851 - 867. [Abstract] [Full Text] [PDF]

				Y.-F. Lee, W.-J. Lin, J. Huang, E. M. Messing, F. L. Chan, G. Wilding, and C. Chang Activation of Mitogen-activated Protein Kinase Pathway by the Antiandrogen Hydroxyflutamide in Androgen Receptor-negative Prostate Cancer Cells Cancer Res., November 1, 2002; 62(21): 6039 - 6044. [Abstract] [Full Text] [PDF]

				P. A. Janne, M. L. Taffaro, R. Salgia, and B. E. Johnson Inhibition of Epidermal Growth Factor Receptor Signaling in Malignant Pleural Mesothelioma Cancer Res., September 15, 2002; 62(18): 5242 - 5247. [Abstract] [Full Text] [PDF]

				J. Baselga Why the Epidermal Growth Factor Receptor? The Rationale for Cancer Therapy Oncologist, August 15, 2002; 7(90004): 2 - 8. [Abstract] [Full Text] [PDF]

				H. Li, S. Velasco-Miguel, W. C. Vass, L. F. Parada, and J. E. DeClue Epidermal Growth Factor Receptor Signaling Pathways Are Associated with Tumorigenesis in the Nf1:p53 Mouse Tumor Model Cancer Res., August 1, 2002; 62(15): 4507 - 4513. [Abstract] [Full Text] [PDF]

				G. K. Dy and A. A. Adjei Novel Targets for Lung Cancer Therapy: Part I J. Clin. Oncol., June 15, 2002; 20(12): 2881 - 2894. [Abstract] [Full Text] [PDF]

				T. Karashima, P. Sweeney, J. W. Slaton, S. J. Kim, D. Kedar, J. I. Izawa, Z. Fan, C. Pettaway, D. J. Hicklin, T. Shuin, et al. Inhibition of Angiogenesis by the Antiepidermal Growth Factor Receptor Antibody ImClone C225 in Androgen-independent Prostate Cancer Growing Orthotopically in Nude Mice Clin. Cancer Res., May 1, 2002; 8(5): 1253 - 1264. [Abstract] [Full Text] [PDF]

				S. R. Chinni and F. H. Sarkar Akt Inactivation Is a Key Event in Indole-3-carbinol-induced Apoptosis in PC-3 Cells Clin. Cancer Res., April 1, 2002; 8(4): 1228 - 1236. [Abstract] [Full Text] [PDF]

				F. Ciardiello and G. Tortora A Novel Approach in the Treatment of Cancer: Targeting the Epidermal Growth Factor Receptor Clin. Cancer Res., October 1, 2001; 7(10): 2958 - 2970. [Abstract] [Full Text] [PDF]

				C. L. Arteaga The Epidermal Growth Factor Receptor: From Mutant Oncogene in Nonhuman Cancers to Therapeutic Target in Human Neoplasia J. Clin. Oncol., September 15, 2001; 19(90001): 32s - 40. [Abstract] [Full Text] [PDF]

				Y.-J. Ko, E. J. Small, F. Kabbinavar, A. Chachoua, S. Taneja, D. Reese, A. DePaoli, A. Hannah, S. P. Balk, and G. J. Bubley A Multi-Institutional Phase II Study of SU101, a Platelet-derived Growth Factor Receptor Inhibitor, for Patients with Hormone-Refractory Prostate Cancer Clin. Cancer Res., April 1, 2001; 7(4): 800 - 805. [Abstract] [Full Text]

				X. Zi, R. P. Singh, and R. Agarwal Impairment of erbB1 receptor and fluid-phase endocytosis and associated mitogenic signaling by inositol hexaphosphate in human prostate carcinoma DU145 cells Carcinogenesis, December 1, 2000; 21(12): 2225 - 2235. [Abstract] [Full Text] [PDF]

				S.-M. Huang and P. M. Harari Modulation of Radiation Response after Epidermal Growth Factor Receptor Blockade in Squamous Cell Carcinomas: Inhibition of Damage Repair, Cell Cycle Kinetics, and Tumor Angiogenesis Clin. Cancer Res., June 1, 2000; 6(6): 2166 - 2174. [Abstract] [Full Text]

				H. A. Lane, I. Beuvink, A. B. Motoyama, J. M. Daly, R. M. Neve, and N. E. Hynes ErbB2 Potentiates Breast Tumor Proliferation through Modulation of p27Kip1-Cdk2 Complex Formation: Receptor Overexpression Does Not Determine Growth Dependency Mol. Cell. Biol., May 1, 2000; 20(9): 3210 - 3223. [Abstract] [Full Text]

				A. D. Perera, E. V. Kleymenova, and C. L. Walker Requirement for the von Hippel-Lindau Tumor Suppressor Gene for Functional Epidermal Growth Factor Receptor Blockade by Monoclonal Antibody C225 in Renal Cell Carcinoma Clin. Cancer Res., April 1, 2000; 6(4): 1518 - 1523. [Abstract] [Full Text]

				D. Busse, R. S. Doughty, T. T. Ramsey, W. E. Russell, J. O. Price, W. M. Flanagan, L. K. Shawver, and C. L. Arteaga Reversible G1 Arrest Induced by Inhibition of the Epidermal Growth Factor Receptor Tyrosine Kinase Requires Up-regulation of p27KIP1 Independent of MAPK Activity J. Biol. Chem., March 15, 2000; 275(10): 6987 - 6995. [Abstract] [Full Text] [PDF]

				J. Mendelsohn Blockade of Receptors for Growth Factors: An Anticancer Therapy -- The Fourth Annual Joseph H. Burchenal American Association for Cancer Research Clinical Research Award Lecture Clin. Cancer Res., March 1, 2000; 6(3): 747 - 753. [Full Text]

				P. M. Harari and S.-M. Huang Modulation of Molecular Targets to Enhance Radiation Clin. Cancer Res., February 1, 2000; 6(2): 323 - 325. [Full Text]

				X.-F. Le, A. McWatters, J. Wiener, J.-Y. Wu, G. B. Mills, and R. C. Bast Jr. Anti-HER2 Antibody and Heregulin Suppress Growth of HER2-Overexpressing Human Breast Cancer Cells through Different Mechanisms Clin. Cancer Res., January 1, 2000; 6(1): 260 - 270. [Abstract] [Full Text]

				D. Ye, J. Mendelsohn, and Z. Fan Androgen and Epidermal Growth Factor Down-Regulate Cyclin-dependent Kinase Inhibitor p27Kip1 and Costimulate Proliferation of MDA PCa 2a and MDA PCa 2b Prostate Cancer Cells Clin. Cancer Res., August 1, 1999; 5(8): 2171 - 2177. [Abstract] [Full Text] [PDF]

				S.-M. Huang, J. M. Bock, and P. M. Harari Epidermal Growth Factor Receptor Blockade with C225 Modulates Proliferation, Apoptosis, and Radiosensitivity in Squamous Cell Carcinomas of the Head and Neck Cancer Res., April 1, 1999; 59(8): 1935 - 1940. [Abstract] [Full Text] [PDF]

				F. Ciardiello, R. Bianco, V. Damiano, S. De Lorenzo, S. Pepe, S. De Placido, Z. Fan, J. Mendelsohn, A. R. Bianco, and G. Tortora Antitumor Activity of Sequential Treatment with Topotecan and Anti-Epidermal Growth Factor Receptor Monoclonal Antibody C225 Clin. Cancer Res., April 1, 1999; 5(4): 909 - 916. [Abstract] [Full Text] [PDF]

				A.-E. Al Moustafa, C. Yansouni, M. A. Alaoui-Jamali, and M. O'Connor-McCourt Up-Regulation of E-Cadherin by an Anti-Epidermal Growth Factor Receptor Monoclonal Antibody in Lung Cancer Cell Lines Clin. Cancer Res., March 1, 1999; 5(3): 681 - 686. [Abstract] [Full Text] [PDF]

				T. Putz, Z. Culig, I. E. Eder, C. Nessler-Menardi, G. Bartsch, H. Grunicke, F. Uberall, and H. Klocker Epidermal Growth Factor (EGF) Receptor Blockade Inhibits the Action of EGF, Insulin-like Growth Factor I, and a Protein Kinase A Activator on the Mitogen-activated Protein Kinase Pathway in Prostate Cancer Cell Lines Cancer Res., January 1, 1999; 59(1): 227 - 233. [Abstract] [Full Text] [PDF]

				F. Wang, V. M. Weaver, O. W. Petersen, C. A. Larabell, S. Dedhar, P. Briand, R. Lupu, and M. J. Bissell Reciprocal interactions between beta 1-integrin and epidermal growth factor receptor in three-dimensional basement membrane breast cultures: A different perspective in epithelial biology PNAS, December 8, 1998; 95(25): 14821 - 14826. [Abstract] [Full Text] [PDF]

				B. St. Croix, C. Sheehan, J. W. Rak, V. A. Florenes, J. M. Slingerland, and R. S. Kerbel E-Cadherin-dependent Growth Suppression is Mediated by the Cyclin-dependent Kinase Inhibitor p27KIP1 J. Cell Biol., July 27, 1998; 142(2): 557 - 571. [Abstract] [Full Text] [PDF]

				J. M. Kokontis, N. Hay, and S. Liao Progression of LNCaP Prostate Tumor Cells during Androgen Deprivation: Hormone-Independent Growth, Repression of Proliferation by Androgen, and Role for p27Kip1 in Androgen-Induced Cell Cycle Arrest Mol. Endocrinol., July 1, 1998; 12(7): 941 - 953. [Abstract] [Full Text]

				K. Szepeshazi, A. V. Schally, G. Halmos, N. Lamharzi, K. Groot, and J. E. Horvath A single in vivo administration of bombesin antagonist RC-3095 reduces the levels and mRNA expression of epidermal growth factor receptors in MXT mouse mammary cancers PNAS, September 30, 1997; 94(20): 10913 - 10918. [Abstract] [Full Text] [PDF]