This Article Full Text 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 Tome, M. E. Articles by Briehl, M. M. Search for Related Content PubMed PubMed Citation Articles by Tome, M. E. Articles by Briehl, M. M.

Catalase-overexpressing Thymocytes Are Resistant to Glucocorticoid-induced Apoptosis and Exhibit Increased Net Tumor Growth¹

Departments of Pathology [M. E. T., G. P., M. M. B.], Pharmacology [A. F. B., G. P.], and Microbiology and Immunology [C. M. P.], University of Arizona, Tucson, Arizona 85724

Glucocorticoids are used for the treatment of lymphoid neoplasms, taking advantage of the well-known ability of these compounds to cause apoptosis in lymphoid tissues. Previously, we have shown that dexamethasone, a synthetic glucocorticoid, causes a down-regulation of several antioxidant defense enzymes and proteins, including catalase and thioredoxin, concomitant with the induction of apoptosis in WEHI7.2 mouse thymoma cells. To test whether this down-regulation plays a critical role in the mechanism of steroid-induced apoptosis, WEHI7.2 cells were transfected with rat catalase. Two clones, expressing 1.4-fold and 2.0-fold higher catalase specific activity, respectively, when compared with vector-only transfectants were selected for further study. An increase to 1.4-fold parental cell catalase activity delayed cell loss after dexamethasone treatment, whereas a 2.0-fold parental catalase activity prevented dexamethasone-induced cell loss for 48 h after treatment. Dexamethasone treatment of the WEHI7.2 cells stimulated a release of cytochrome c into the cytosol. Catalase-overexpressing cells showed a delay or lack of cytochrome c release from the mitochondria, which correlated temporally with the delay or prevention of cell loss in the culture after dexamethasone treatment. A decreased amount of cell death from WEHI7.2 cells overexpressing catalase was also seen in tumor xenografts in severe combined immunodeficient mice when compared with tumors from vector-only transfected cells. Similarly, thioredoxin-overexpressing WEHI7.2 cells, shown previously to be apoptosis resistant, showed decreased cell death in tumor xenografts. This resulted in larger tumors from cells overexpressing these proteins. Cell death in control transfectant tumor xenografts was primarily attributable to apoptosis. In contrast, the cell death we observed in tumors from thioredoxin- or catalase-overexpressing cells had a higher frequency of a nonapoptotic, nonnecrotic type of cell death termed para-apoptosis. These data suggest that: (a) oxidative stress plays a critical role in steroid-induced apoptosis prior to the commitment of the cells to undergo apoptosis; and (b) resistance to oxidative stress can contribute to tumor growth.

This article has been cited by other articles:

				W. BECHTEL and G. BAUER Catalase Protects Tumor Cells from Apoptosis Induction by Intercellular ROS Signaling Anticancer Res, November 1, 2009; 29(11): 4541 - 4557. [Abstract] [Full Text] [PDF]

				O. Cohen, S. Kfir-Erenfeld, R. Spokoini, Y. Zilberman, E. Yefenof, and R. V. Sionov Nitric oxide cooperates with glucocorticoids in thymic epithelial cell-mediated apoptosis of double positive thymocytes Int. Immunol., October 1, 2009; 21(10): 1113 - 1123. [Abstract] [Full Text] [PDF]

				M. C. Jaramillo, J. B. Frye, J. D. Crapo, M. M. Briehl, and M. E. Tome Increased Manganese Superoxide Dismutase Expression or Treatment with Manganese Porphyrin Potentiates Dexamethasone-Induced Apoptosis in Lymphoma Cells Cancer Res., July 1, 2009; 69(13): 5450 - 5457. [Abstract] [Full Text] [PDF]

				M. C. Davis, K. S. McColl, F. Zhong, Z. Wang, M. H. Malone, and C. W. Distelhorst Dexamethasone-induced Inositol 1,4,5-Trisphosphate Receptor Elevation in Murine Lymphoma Cells Is Not Required for Dexamethasone-mediated Calcium Elevation and Apoptosis J. Biol. Chem., April 18, 2008; 283(16): 10357 - 10365. [Abstract] [Full Text] [PDF]

				H.-H. S. Chow, I. A. Hakim, D. R. Vining, J. A. Crowell, M. E. Tome, J. Ranger-Moore, C. A. Cordova, D. M. Mikhael, M. M. Briehl, and D. S. Alberts Modulation of Human Glutathione S-Transferases by Polyphenon E Intervention Cancer Epidemiol. Biomarkers Prev., August 1, 2007; 16(8): 1662 - 1666. [Abstract] [Full Text] [PDF]

				K. S. Rajapaksa, I. G. Sipes, and P. B. Hoyer Involvement of Microsomal Epoxide Hydrolase Enzyme in Ovotoxicity Caused by 7,12-Dimethylbenz[a]anthracene Toxicol. Sci., April 1, 2007; 96(2): 327 - 334. [Abstract] [Full Text] [PDF]

				M. H. Malone, Z. Wang, and C. W. Distelhorst The Glucocorticoid-induced Gene tdag8 Encodes a Pro-apoptotic G Protein-coupled Receptor Whose Activation Promotes Glucocorticoid-induced Apoptosis J. Biol. Chem., December 17, 2004; 279(51): 52850 - 52859. [Abstract] [Full Text] [PDF]

				S. P. Hussain, P. Amstad, P. He, A. Robles, S. Lupold, I. Kaneko, M. Ichimiya, S. Sengupta, L. Mechanic, S. Okamura, et al. p53-Induced Up-Regulation of MnSOD and GPx but not Catalase Increases Oxidative Stress and Apoptosis Cancer Res., April 1, 2004; 64(7): 2350 - 2356. [Abstract] [Full Text] [PDF]

				E. J. Houwerzijl, N. R. Blom, J. J. L. van der Want, M. T. Esselink, J. J. Koornstra, J. W. Smit, H. Louwes, E. Vellenga, and J. Th. M. de Wolf Ultrastructural study shows morphologic features of apoptosis and para-apoptosis in megakaryocytes from patients with idiopathic thrombocytopenic purpura Blood, January 15, 2004; 103(2): 500 - 506. [Abstract] [Full Text] [PDF]

				N. Tonomura, K. McLaughlin, L. Grimm, R. A. Goldsby, and B. A. Osborne Glucocorticoid-Induced Apoptosis of Thymocytes: Requirement of Proteasome-Dependent Mitochondrial Activity J. Immunol., March 1, 2003; 170(5): 2469 - 2478. [Abstract] [Full Text] [PDF]