Cell Growth & Differentiation, Vol 8, Issue 3 343-352, Copyright © 1997 by American Association of Cancer Research

ARTICLES

Induction of apoptosis and inhibition of cell growth are independent responses to interferon-alpha in hematopoietic cell lines

O Sangfelt, S Erickson, J Castro, T Heiden, S Einhorn and D Grander
Department of Oncology/Pathology, Karolinska Hospital and Institute, Stockholm, Sweden.

IFNs are capable of modulating a variety of cellular responses, including cell growth and apoptosis. The prospective connections between these two biological responses are not fully understood, and the molecular mechanisms underlying the effects of IFNs on these processes are not completely defined. We have investigated the relationship between IFN-alpha-induced apoptosis and cell cycle arrest in three hematopoietic cell lines, Daudi, U-266, and H9. It was found that IFN-alpha was a rapid and potent inducer of apoptosis in H9 and U-266 cells, whereas IFN-alpha-induced cell cycle arrest in Daudi cells is not associated with the onset of apoptosis. In H9 cells, apoptosis occurs without a preceding cell cycle block, whereas in U-266 cells, apoptosis occurs subsequent to G1 arrest. Cell cycle arrest per se, induced by serum starvation or treatment with aphidicolin, had only minor effects on the viability of these cell lines and did not abrogate the apoptosis-inducing capacity of IFN-alpha. Additionally, IFN-alpha-induced apoptosis occurred in cells from all cell cycle phases. Thus, we conclude that IFN-alpha-induced apoptosis seems to occur independent of cell growth inhibition. There were no changes in Bcl-2 or Bax protein levels that could account for the apoptosis-inducing effects of IFN-alpha in these cell lines. Moreover, examination of p53 status suggests that IFN-alpha-induced apoptosis in the U-266 and H9 cell lines occurs through a p53-independent pathway.

This article has been cited by other articles:

				A. J. Scarzello, A. L. Romero-Weaver, S. G. Maher, T. D. Veenstra, M. Zhou, A. Qin, R. P. Donnelly, F. Sheikh, and A. M. Gamero A Mutation in the SH2 Domain of STAT2 Prolongs Tyrosine Phosphorylation of STAT1 and Promotes Type I IFN-induced Apoptosis Mol. Biol. Cell, July 1, 2007; 18(7): 2455 - 2462. [Abstract] [Full Text] [PDF]

				W. Jiang, C. W. Bell, and D. S. Pisetsky The Relationship between Apoptosis and High-Mobility Group Protein 1 Release from Murine Macrophages Stimulated with Lipopolysaccharide or Polyinosinic-Polycytidylic Acid J. Immunol., May 15, 2007; 178(10): 6495 - 6503. [Abstract] [Full Text] [PDF]

				R. Potla, T. Koeck, J. Wegrzyn, S. Cherukuri, K. Shimoda, D. P. Baker, J. Wolfman, S. M. Planchon, C. Esposito, B. Hoit, et al. Tyk2 Tyrosine Kinase Expression Is Required for the Maintenance of Mitochondrial Respiration in Primary Pro-B Lymphocytes Mol. Cell. Biol., November 15, 2006; 26(22): 8562 - 8571. [Abstract] [Full Text] [PDF]

				P. T. N. Sarkis, S. Ying, R. Xu, and X.-F. Yu STAT1-Independent Cell Type-Specific Regulation of Antiviral APOBEC3G by IFN-{alpha} J. Immunol., October 1, 2006; 177(7): 4530 - 4540. [Abstract] [Full Text] [PDF]

				S. Elankumaran, D. Rockemann, and S. K. Samal Newcastle Disease Virus Exerts Oncolysis by both Intrinsic and Extrinsic Caspase-Dependent Pathways of Cell Death. J. Virol., August 1, 2006; 80(15): 7522 - 7534. [Abstract] [Full Text] [PDF]

				A. M. Gamero, R. Potla, J. Wegrzyn, M. Szelag, A. E. Edling, K. Shimoda, D. C. Link, J. Dulak, D. P. Baker, Y. Tanabe, et al. Activation of Tyk2 and Stat3 Is Required for the Apoptotic Actions of Interferon-beta in Primary Pro-B Cells J. Biol. Chem., June 16, 2006; 281(24): 16238 - 16244. [Abstract] [Full Text] [PDF]

				Y. Takemoto, H. Yano, S. Momosaki, S. Ogasawara, N. Nishida, S. Kojiro, T. Kamura, and M. Kojiro Antiproliferative Effects of Interferon-{alpha}Con1 on Ovarian Clear Cell Adenocarcinoma In vitro and In vivo Clin. Cancer Res., November 1, 2004; 10(21): 7418 - 7426. [Abstract] [Full Text] [PDF]

				E. Dondi, G. Roue, V. J. Yuste, S. A. Susin, and S. Pellegrini A Dual Role of IFN-{alpha} in the Balance between Proliferation and Death of Human CD4+ T Lymphocytes during Primary Response J. Immunol., September 15, 2004; 173(6): 3740 - 3747. [Abstract] [Full Text] [PDF]

				R. Sandoval, J. Xue, M. Pilkinton, D. Salvi, H. Kiyokawa, and O. R. Colamonici Different Requirements for the Cytostatic and Apoptotic Effects of Type I Interferons: INDUCTION OF APOPTOSIS REQUIRES ARF BUT NOT p53 IN OSTEOSARCOMA CELL LINES J. Biol. Chem., July 30, 2004; 279(31): 32275 - 32280. [Abstract] [Full Text] [PDF]

				L. Thyrell, L. Hjortsberg, V. Arulampalam, T. Panaretakis, S. Uhles, M. Dagnell, B. Zhivotovsky, I. Leibiger, D. Grander, and K. Pokrovskaja Interferon {alpha}-induced Apoptosis in Tumor Cells Is Mediated through the Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Signaling Pathway J. Biol. Chem., June 4, 2004; 279(23): 24152 - 24162. [Abstract] [Full Text] [PDF]

				V. S. Cull, P. A. Tilbrook, E. J. Bartlett, N. L. Brekalo, and C. M. James Type I interferon differential therapy for erythroleukemia: specificity of STAT activation Blood, April 1, 2003; 101(7): 2727 - 2735. [Abstract] [Full Text] [PDF]

				L. Tracey, R. Villuendas, P. Ortiz, A. Dopazo, I. Spiteri, L. Lombardia, J. L. Rodriguez-Peralto, J. Fernandez-Herrera, A. Hernandez, J. Fraga, et al. Identification of Genes Involved in Resistance to Interferon-{alpha} in Cutaneous T-Cell Lymphoma Am. J. Pathol., November 1, 2002; 161(5): 1825 - 1837. [Abstract] [Full Text] [PDF]

				Q. Chen, B. Gong, A. S. Mahmoud-Ahmed, A. Zhou, E. D. Hsi, M. Hussein, and A. Almasan Apo2L/TRAIL and Bcl-2-related proteins regulate type I interferon-induced apoptosis in multiple myeloma Blood, October 1, 2001; 98(7): 2183 - 2192. [Abstract] [Full Text] [PDF]

				M. Chawla-Sarkar, D. W. Leaman, and E. C. Borden Preferential Induction of Apoptosis by Interferon (IFN)-{beta} Compared with IFN-{{alpha}}2: Correlation with TRAIL/Apo2L Induction in Melanoma Cell Lines Clin. Cancer Res., June 1, 2001; 7(6): 1821 - 1831. [Abstract] [Full Text] [PDF]

				S. F. Matin, R. R. Rackley, P. C. Sadhukhan, M. S. Kim, A. C. Novick, and S. K. Bandyopadhyay Impaired {{alpha}}-Interferon Signaling in Transitional Cell Carcinoma: Lack of p48 Expression in 5637 Cells Cancer Res., March 1, 2001; 61(5): 2261 - 2266. [Abstract] [Full Text]

				D. Xu, S. Erickson, M. Szeps, A. Gruber, O. Sangfelt, S. Einhorn, P. Pisa, and D. Grander Interferon alpha down-regulates telomerase reverse transcriptase and telomerase activity in human malignant and nonmalignant hematopoietic cells Blood, December 15, 2000; 96(13): 4313 - 4318. [Abstract] [Full Text] [PDF]

				D. Zella, O. Barabitskaja, L. Casareto, F. Romerio, P. Secchiero, M. S. Reitz Jr., R. C. Gallo, and F. F. Weichold Recombinant IFN-{alpha} (2b) Increases the Expression of Apoptosis Receptor CD95 and Chemokine Receptors CCR1 and CCR3 in Monocytoid Cells J. Immunol., September 15, 1999; 163(6): 3169 - 3175. [Abstract] [Full Text] [PDF]

				S. Erickson, O. Sangfelt, J. Castro, M. Heyman, S. Einhorn, and D. Grandér Interferon-{{alpha}} Inhibits Proliferation in Human T Lymphocytes by Abrogation of Interleukin 2-induced Changes in Cell Cycle-regulatory Proteins Cell Growth Differ., August 1, 1999; 10(8): 575 - 582. [Abstract] [Full Text]

				A. M. Gamero and A. C. Larner Vanadate Facilitates Interferon alpha -mediated Apoptosis That Is Dependent on the Jak/Stat Pathway J. Biol. Chem., April 20, 2001; 276(17): 13547 - 13553. [Abstract] [Full Text] [PDF]