Cell Growth & Differentiation, Vol 8, Issue 3 269-274, Copyright © 1997 by American Association of Cancer Research

ARTICLES

Decreased tumorigenicity of a human colon adenocarcinoma cell line by an antisense expression vector specific for c-Src

CA Staley, NU Parikh and GE Gallick
Department of Tumor Biology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.

In greater than 80% of colon tumors and established cell lines, the specific activities of the protein tyrosine kinases pp60(c-src) and pp62(c-yes) are increased with respect to normal colonic epithelial cells. However, no mutations in either gene have been identified in colon tumors. Therefore, the possible biological consequences of activations of these protein tyrosine kinases in colon tumors have been unclear. To determine if pp60(c-src) activation affects growth and tumorigenicity of established colon tumor cell lines, an antisense expression vector that specifically reduces pp60(c-src) expression was constructed. The vector was transfected into HT 29 cells, an established colon tumor cell line in which both pp60(c-src) and pp62(c-yes) are activated. Two stable subclones were isolated in which pp60(c-src) but not pp62(c-yes) expression and activity were reduced. These established cell lines proliferated more slowly than parental cells proportionately to reduction in pp60(c-src) expression. When injected into nude mice, antisense transfected cells formed slow-growing tumors; however, the rate of tumor growth was reduced far greater than would be predicted from decreased proliferation rates in tissue culture. In contrast, stable subclones transfected with a comparable "sense" expression vector were unaltered in growth rates in tissue culture and in nude mice with respect to parental HT 29 cells. These data demonstrate that the activation of pp60(c-src) alone contributes to the tumorigenicity of HT 29 cells, a cell line widely used as a model for biological properties of colon carcinoma. Furthermore, because pp60(c-src) and pp62(c-yes) appear redundant to the growth regulation of normal colonic epithelial cells, the data suggest that src-specific inhibitors might be of therapeutic value for colon cancer.

This article has been cited by other articles:

				S. Zhu, J. D. Bjorge, and D. J. Fujita PTP1B Contributes to the Oncogenic Properties of Colon Cancer Cells through Src Activation Cancer Res., November 1, 2007; 67(21): 10129 - 10137. [Abstract] [Full Text] [PDF]

				Y. Shen, P. R. Khusial, X. Li, H. Ichikawa, A. P. Moreno, and G. S. Goldberg Src Utilizes Cas to Block Gap Junctional Communication Mediated by Connexin43 J. Biol. Chem., June 29, 2007; 282(26): 18914 - 18921. [Abstract] [Full Text] [PDF]

				A. Serrels, I. R.J. Macpherson, T.R. J. Evans, F. Y. Lee, E. A. Clark, O. J. Sansom, G. H. Ashton, M. C. Frame, and V. G. Brunton Identification of potential biomarkers for measuring inhibition of Src kinase activity in colon cancer cells following treatment with dasatinib Mol. Cancer Ther., December 1, 2006; 5(12): 3014 - 3022. [Abstract] [Full Text] [PDF]

				K S Kimbro and J W Simons Hypoxia-inducible factor-1 in human breast and prostate cancer. Endocr. Relat. Cancer, September 1, 2006; 13(3): 739 - 749. [Abstract] [Full Text] [PDF]

				A. M. L. Coluccia, D. Benati, H. Dekhil, A. De Filippo, C. Lan, and C. Gambacorti-Passerini SKI-606 Decreases Growth and Motility of Colorectal Cancer Cells by Preventing pp60(c-Src)-Dependent Tyrosine Phosphorylation of {beta}-Catenin and Its Nuclear Signaling Cancer Res., February 15, 2006; 66(4): 2279 - 2286. [Abstract] [Full Text] [PDF]

				J. M. Summy, J. G. Trevino, D. P. Lesslie, C. H. Baker, W. C. Shakespeare, Y. Wang, R. Sundaramoorthi, C. A. Metcalf III, J. A. Keats, T. K. Sawyer, et al. AP23846, a novel and highly potent Src family kinase inhibitor, reduces vascular endothelial growth factor and interleukin-8 expression in human solid tumor cell lines and abrogates downstream angiogenic processes Mol. Cancer Ther., December 1, 2005; 4(12): 1900 - 1911. [Abstract] [Full Text] [PDF]

				F. M. Johnson, B. Saigal, M. Talpaz, and N. J. Donato Dasatinib (BMS-354825) Tyrosine Kinase Inhibitor Suppresses Invasion and Induces Cell Cycle Arrest and Apoptosis of Head and Neck Squamous Cell Carcinoma and Non-Small Cell Lung Cancer Cells Clin. Cancer Res., October 1, 2005; 11(19): 6924 - 6932. [Abstract] [Full Text] [PDF]

				J. M. Golas, J. Lucas, C. Etienne, J. Golas, C. Discafani, L. Sridharan, E. Boghaert, K. Arndt, F. Ye, D. H. Boschelli, et al. SKI-606, a Src/Abl Inhibitor with In vivo Activity in Colon Tumor Xenograft Models Cancer Res., June 15, 2005; 65(12): 5358 - 5364. [Abstract] [Full Text] [PDF]

				V. G. Brunton, E. Avizienyte, V. J. Fincham, B. Serrels, C. A. Metcalf III, T. K. Sawyer, and M. C. Frame Identification of Src-Specific Phosphorylation Site on Focal Adhesion Kinase: Dissection of the Role of Src SH2 and Catalytic Functions and Their Consequences for Tumor Cell Behavior Cancer Res., February 15, 2005; 65(4): 1335 - 1342. [Abstract] [Full Text] [PDF]

				B. Olszewska-Pazdrak, C. M. Townsend Jr., and M. R. Hellmich Agonist-independent Activation of Src Tyrosine Kinase by a Cholecystokinin-2 (CCK2) Receptor Splice Variant J. Biol. Chem., September 24, 2004; 279(39): 40400 - 40404. [Abstract] [Full Text] [PDF]

				M. S. Duxbury, H. Ito, M. J. Zinner, S. W. Ashley, and E. E. Whang Inhibition of Src Tyrosine Kinase Impairs Inherent and Acquired Gemcitabine Resistance in Human Pancreatic Adenocarcinoma Cells Clin. Cancer Res., April 1, 2004; 10(7): 2307 - 2318. [Abstract] [Full Text] [PDF]

				D. D. Boyd, H. Wang, H. Avila, N. U. Parikh, H. Kessler, V. Magdolen, and G. E. Gallick Combination of an Src Kinase Inhibitor with a Novel Pharmacological Antagonist of the Urokinase Receptor Diminishes in Vitro Colon Cancer Invasiveness Clin. Cancer Res., February 15, 2004; 10(4): 1545 - 1555. [Abstract] [Full Text] [PDF]

				A. Myoui, R. Nishimura, P. J. Williams, T. Hiraga, D. Tamura, T. Michigami, G. R. Mundy, and T. Yoneda C-Src Tyrosine Kinase Activity Is Associated with Tumor Colonization in Bone and Lung in an Animal Model of Human Breast Cancer Metastasis Cancer Res., August 15, 2003; 63(16): 5028 - 5033. [Abstract] [Full Text] [PDF]

				V. M. Golubovskaya, S. Gross, A. S. Kaur, R. I. Wilson, L.-H. Xu, X. H. Yang, and W. G. Cance Simultaneous Inhibition of Focal Adhesion Kinase and Src Enhances Detachment and Apoptosis in Colon Cancer Cell Lines Mol. Cancer Res., August 1, 2003; 1(10): 755 - 764. [Abstract] [Full Text] [PDF]

				M. H. Herynk, O. Stoeltzing, N. Reinmuth, N. U. Parikh, R. Abounader, J. Laterra, R. Radinsky, L. M. Ellis, and G. E. Gallick Down-Regulation of c-Met Inhibits Growth in the Liver of Human Colorectal Carcinoma Cells Cancer Res., June 1, 2003; 63(11): 2990 - 2996. [Abstract] [Full Text] [PDF]

				A. D. Laird, G. Li, K. G. Moss, R. A. Blake, M. A. Broome, J. M. Cherrington, and D. B. Mendel Src Family Kinase Activity Is Required for Signal Tranducer and Activator of Transcription 3 and Focal Adhesion Kinase Phosphorylation and Vascular Endothelial Growth Factor Signaling in Vivo and for Anchorage-dependent and -independent Growth of Human Tumor Cells Mol. Cancer Ther., May 1, 2003; 2(5): 461 - 469. [Abstract] [Full Text] [PDF]

				J.-S. Nam, Y. Ino, M. Sakamoto, and S. Hirohashi Src Family Kinase Inhibitor PP2 Restores the E-Cadherin/Catenin Cell Adhesion System in Human Cancer Cells and Reduces Cancer Metastasis Clin. Cancer Res., July 1, 2002; 8(7): 2430 - 2436. [Abstract] [Full Text] [PDF]

				J. R. Wiener, K. Nakano, R. P. Kruzelock, C. D. Bucana, R. C. Bast Jr., and G. E. Gallick Decreased Src Tyrosine Kinase Activity Inhibits Malignant Human Ovarian Cancer Tumor Growth in a Nude Mouse Model Clin. Cancer Res., August 1, 1999; 5(8): 2164 - 2170. [Abstract] [Full Text] [PDF]

				R. Hernandez-Alcoceba, F. Fernandez, and J. C. Lacal In Vivo Antitumor Activity of Choline Kinase Inhibitors: A Novel Target for Anticancer Drug Discovery Cancer Res., July 1, 1999; 59(13): 3112 - 3118. [Abstract] [Full Text] [PDF]

				L. M. Ellis, C. A. Staley, W. Liu, R. Y. D. Fleming, N. U. Parikh, C. D. Bucana, and G. E. Gallick Down-regulation of Vascular Endothelial Growth Factor in a Human Colon Carcinoma Cell Line Transfected with an Antisense Expression Vector Specific for c-src J. Biol. Chem., January 9, 1998; 273(2): 1052 - 1057. [Abstract] [Full Text] [PDF]

				K. Bonham, S. A. Ritchie, S. M. Dehm, K. Snyder, and F. M. Boyd An Alternative, Human SRC Promoter and Its Regulation by Hepatic Nuclear Factor-1alpha J. Biol. Chem., November 22, 2000; 275(48): 37604 - 37611. [Abstract] [Full Text] [PDF]