This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services 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 Gibson, E. M. Articles by Gibson, S. B. Search for Related Content PubMed PubMed Citation Articles by Gibson, E. M. Articles by Gibson, S. B.

Epidermal Growth Factor Protects Epithelial-derived Cells from Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis by Inhibiting Cytochrome c Release¹

Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Manitoba, Canada R3E 0V9

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in combination with chemotherapeutic drugs induces a synergistic apoptotic response in cancer cells. TRAIL death receptors have also been implicated in chemotherapeutic drug-induced apoptosis. This has lead to TRAIL being proposed as a potential cancer treatment. In nude mice injected with human tumors, TRAIL reduces the size of these tumors without toxic side effects. We demonstrate that the epidermal growth factor (EGF) stimulation of human embryonic kidney cells HEK 293 and breast cancer cell line MDA MB 231 effectively protects these cells from TRAIL-induced apoptosis in a dose-dependent manner. This stimulation blocks apoptosis by inhibiting TRAIL-mediated cytochrome c release from the mitochondria and caspase 3-like activation. EGF survival response involves the activation of AKT. Expression of activated AKT was sufficient to block TRAIL-induced apoptosis, and kinase-inactive AKT expression blocked EGF-protective response. In contrast, inhibition of EGF stimulation of extracellular-regulated kinase (ERK) activity did not affect EGF protection. These findings indicate that EGF receptor activation provides a survival response against TRAIL-induced apoptosis by inhibiting mitochondrial cytochrome c release that is mediated by AKT activation in epithelial-derived cells.

This article has been cited by other articles:

				S. Maddika, S. R. Ande, E. Wiechec, L. L. Hansen, S. Wesselborg, and M. Los Akt-mediated phosphorylation of CDK2 regulates its dual role in cell cycle progression and apoptosis J. Cell Sci., April 1, 2008; 121(7): 979 - 988. [Abstract] [Full Text] [PDF]

				Y. Chen, E. McMillan-Ward, J. Kong, S. J. Israels, and S. B. Gibson Mitochondrial electron-transport-chain inhibitors of complexes I and II induce autophagic cell death mediated by reactive oxygen species J. Cell Sci., December 1, 2007; 120(23): 4155 - 4166. [Abstract] [Full Text] [PDF]

				S. Kato, A. Sadarangani, S. Lange, M. Villalon, J. Branes, J. J Brosens, G. I Owen, and M. Cuello The oestrogen metabolite 2-methoxyoestradiol alone or in combination with tumour necrosis factor-related apoptosis-inducing ligand mediates apoptosis in cancerous but not healthy cells of the human endometrium Endocr. Relat. Cancer, June 1, 2007; 14(2): 351 - 368. [Abstract] [Full Text] [PDF]

				A. Srirangam, R. Mitra, M. Wang, J. C. Gorski, S. Badve, L. Baldridge, J. Hamilton, H. Kishimoto, J. Hawes, L. Li, et al. Effects of HIV Protease Inhibitor Ritonavir on Akt-Regulated Cell Proliferation in Breast Cancer Clin. Cancer Res., March 15, 2006; 12(6): 1883 - 1896. [Abstract] [Full Text] [PDF]

				L. M. Howells, E. A. Hudson, and M. M. Manson Inhibition of Phosphatidylinositol 3-Kinase/Protein Kinase B Signaling Is Not Sufficient to Account for Indole-3-Carbinol-Induced Apoptosis in Some Breast and Prostate Tumor Cells Clin. Cancer Res., December 1, 2005; 11(23): 8521 - 8527. [Abstract] [Full Text] [PDF]

				R. Shao, D.-F. Lee, Y. Wen, Y. Ding, W. Xia, B. Ping, H. Yagita, B. Spohn, and M.-C. Hung E1A Sensitizes Cancer Cells to TRAIL-Induced Apoptosis through Enhancement of Caspase Activation Mol. Cancer Res., April 1, 2005; 3(4): 219 - 226. [Abstract] [Full Text] [PDF]

				L. A. Knodler, B. B. Finlay, and O. Steele-Mortimer The Salmonella Effector Protein SopB Protects Epithelial Cells from Apoptosis by Sustained Activation of Akt J. Biol. Chem., March 11, 2005; 280(10): 9058 - 9064. [Abstract] [Full Text] [PDF]

				X. Hu, N. Haney, D. Kropp, A. F. Kabore, J. B. Johnston, and S. B. Gibson Lysophosphatidic Acid (LPA) Protects Primary Chronic Lymphocytic Leukemia Cells from Apoptosis through LPA Receptor Activation of the Anti-apoptotic Protein AKT/PKB J. Biol. Chem., March 11, 2005; 280(10): 9498 - 9508. [Abstract] [Full Text] [PDF]

				J. Shi, D. Zheng, Y. Liu, M. H. Sham, P. Tam, F. Farzaneh, and R. Xu Overexpression of Soluble TRAIL Induces Apoptosis in Human Lung Adenocarcinoma and Inhibits Growth of Tumor Xenografts in Nude Mice Cancer Res., March 1, 2005; 65(5): 1687 - 1692. [Abstract] [Full Text] [PDF]

				T. Matsuda, A. Almasan, M. Tomita, J.-n. Uchihara, M. Masuda, K. Ohshiro, N. Takasu, H. Yagita, T. Ohta, and N. Mori Resistance to Apo2 Ligand (Apo2L)/Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)-Mediated Apoptosis and Constitutive Expression of Apo2L/TRAIL in Human T-Cell Leukemia Virus Type 1-Infected T-Cell Lines J. Virol., February 1, 2005; 79(3): 1367 - 1378. [Abstract] [Full Text] [PDF]

				S. Zhougang and R. G. Schnellmann H2O2-induced transactivation of EGF receptor requires Src and mediates ERK1/2, but not Akt, activation in renal cells Am J Physiol Renal Physiol, May 1, 2004; 286(5): F858 - F865. [Abstract] [Full Text] [PDF]

				J. P. Steinbach, A. Klumpp, H. Wolburg, and M. Weller Inhibition of Epidermal Growth Factor Receptor Signaling Protects Human Malignant Glioma Cells from Hypoxia-Induced Cell Death Cancer Res., March 1, 2004; 64(5): 1575 - 1578. [Abstract] [Full Text] [PDF]

				P. P. Manna and W. A. Frazier CD47 Mediates Killing of Breast Tumor Cells via Gi-Dependent Inhibition of Protein Kinase A Cancer Res., February 1, 2004; 64(3): 1026 - 1036. [Abstract] [Full Text] [PDF]

				K. Takeuchi and F. Ito Suppression of Adriamycin-induced Apoptosis by Sustained Activation of the Phosphatidylinositol-3'-OH kinase-Akt Pathway J. Biol. Chem., January 9, 2004; 279(2): 892 - 900. [Abstract] [Full Text] [PDF]

				A. W. Knott, D. P. O'Brien, R. J. Juno, Y. Zhang, J. L. Williams, C. R. Erwin, and B. W. Warner Enterocyte apoptosis after enterectomy in mice is activated independent of the extrinsic death receptor pathway Am J Physiol Gastrointest Liver Physiol, July 7, 2003; 285(2): G404 - G413. [Abstract] [Full Text] [PDF]

				V. Golubovskaya, L. Beviglia, L.-H. Xu, H. S. Earp III, R. Craven, and W. Cance Dual Inhibition of Focal Adhesion Kinase and Epidermal Growth Factor Receptor Pathways Cooperatively Induces Death Receptor-mediated Apoptosis in Human Breast Cancer Cells J. Biol. Chem., October 4, 2002; 277(41): 38978 - 38987. [Abstract] [Full Text] [PDF]