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 Han, Z. Articles by Wyche, J. H. Search for Related Content PubMed PubMed Citation Articles by Han, Z. Articles by Wyche, J. H.

Isolation and Characterization of an Apoptosis-resistant Variant of Human Leukemia HL-60 Cells That Has Switched Expression from Bcl-2 to Bcl-X_L¹

Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island 02912 [Z. H., D. C., E. A. H., J. H. W.], and The Stehlin Foundation for Cancer Research at St. Joseph Hospital, Houston, Texas 77003 [J. E., P. P.]

Human promyelocytic leukemia HL-60 cells treated with 8-chloro-adenosine-3',5'-cyclic monophosphate (8-Cl-cAMP) undergo growth arrest and subsequently die by apoptosis. We describe here the isolation of a variant of HL-60 cells, HCW-2, which was resistant to the cytotoxic effects of 8-Cl-cAMP, but still underwent growth arrest. Thus, HCW-2 cells appeared to be altered in their ability to undergo apoptosis. HCW-2 cells were also completely refractory to the apoptotic action of cycloheximide and staurosporine, two compounds which were very potent inducers of apoptosis in the parental HL-60 cells, suggesting that the resistance to apoptosis was not unique to 8-Cl-cAMP. Western blot analysis demonstrated that the parental HL-60 cells expressed both Bcl-2 and Bax, two factors known to be intimately involved in the control of apoptosis. Surprisingly, HCW-2 cells no longer expressed Bcl-2 protein and paradoxically contained Bax protein at a level that was approximately 50-fold higher than in HL-60 cells. However, Northern and Western analyses indicated that the apoptotic suppressor gene, bcl-x_L, which is not expressed in the parental HL-60 cells, was expressed in HCW-2 cells. Thus, the Bcl-2-independent resistance of HCW-2 cells to apoptotic induction is discussed in terms of the expression of bcl-x_L.

¹ This work was supported by resources provided by Brown University and The Stehlin Foundation for Cancer Research. E. A. H. is a Leukemia Society of American Scholar.

² To whom requests for reprints should be addressed, at J. W. Wilson Laboratory, Brown University, 69 Brown Street, Providence, RI 02912. Phone: (401) 863-3679; Fax: (401) 863-2244; E-mail: Zhiyong_Han@brown.edu.

Received 8/ 8/95. Accepted 1/30/96.

This article has been cited by other articles:

				S. Hussain, A. Pluckthun, T. M. Allen, and U. Zangemeister-Wittke Chemosensitization of carcinoma cells using epithelial cell adhesion molecule-targeted liposomal antisense against bcl-2/bcl-xL Mol. Cancer Ther., December 1, 2006; 5(12): 3170 - 3180. [Abstract] [Full Text] [PDF]

				K. Yamanaka, P. Rocchi, H. Miyake, L. Fazli, B. Vessella, U. Zangemeister-Wittke, and M. E. Gleave A novel antisense oligonucleotide inhibiting several antiapoptotic Bcl-2 family members induces apoptosis and enhances chemosensitivity in androgen-independent human prostate cancer PC3 cells Mol. Cancer Ther., November 1, 2005; 4(11): 1689 - 1698. [Abstract] [Full Text] [PDF]

				O. Gautschi, U. Zangemeister-Wittke, and R. A. Stahel Comment on "A pilot trial of G3139, a bcl-2 antisense oligonucleotide, and paclitaxel in patients with chemorefractory small-cell lung cancer", by C. M. Rudin et al. (Ann Oncol 2002; 13: 539-545) Ann. Onc., January 1, 2003; 14(1): 170 - 170. [Full Text] [PDF]

				Z. Han, W. Wei, S. Dunaway, J. W. Darnowski, P. Calabresi, J. Sedivy, E. A. Hendrickson, K. V. Balan, P. Pantazis, and J. H. Wyche Role of p21 in Apoptosis and Senescence of Human Colon Cancer Cells Treated with Camptothecin J. Biol. Chem., May 3, 2002; 277(19): 17154 - 17160. [Abstract] [Full Text] [PDF]

				O. Gautschi, S. Tschopp, R. A. Olie, S. H. Leech, A. P. Simoes-Wust, A. Ziegler, B. Baumann, B. Odermatt, J. Hall, R. A. Stahel, et al. Activity of a Novel bcl-2/bcl-xL-Bispecific Antisense Oligonucleotide Against Tumors of Diverse Histologic Origins J Natl Cancer Inst, March 21, 2001; 93(6): 463 - 471. [Abstract] [Full Text] [PDF]

				U. Zangemeister-Wittke, S. H. Leech, R. A. Olie, A. P. Simões-Wüst, O. Gautschi, G. H. Luedke, F. Natt, R. Häner, P. Martin, J. Hall, et al. A Novel Bispecific Antisense Oligonucleotide Inhibiting Both bcl-2 and bcl-xL Expression Efficiently Induces Apoptosis in Tumor Cells Clin. Cancer Res., June 1, 2000; 6(6): 2547 - 2555. [Abstract] [Full Text]

				N. Shinoura, Y. Yoshida, M. Nishimura, Y. Muramatsu, A. Asai, T. Kirino, and H. Hamada Expression Level of Bcl-2 Determines Anti- or Proapoptotic Function Cancer Res., August 1, 1999; 59(16): 4119 - 4128. [Abstract] [Full Text] [PDF]

				K. Myung, C. Braastad, D. M. He, and E. A. Hendrickson KARP-1 is induced by DNA damage in a p53- and ataxia telangiectasia mutated-dependent fashion PNAS, June 23, 1998; 95(13): 7664 - 7669. [Abstract] [Full Text] [PDF]

				N. A. Jones, J. Turner, A. J. McIlwrath, R. Brown, and C. Dive Cisplatin- and Paclitaxel-Induced Apoptosis of Ovarian Carcinoma Cells and the Relationship between Bax and Bak Up-Regulation and the Functional Status of p53 Mol. Pharmacol., May 1, 1998; 53(5): 819 - 826. [Abstract] [Full Text]

				C. A. Hsu, A. K. Rishi, X. Su-Li, T. M. Gerald, M. I. Dawson, C. Schiffer, U. Reichert, B. Shroot, G. C. Poirer, and J. A. Fontana Retinoid Induced Apoptosis in Leukemia Cells Through a Retinoic Acid Nuclear Receptor-Independent Pathway Blood, June 15, 1997; 89(12): 4470 - 4479. [Abstract] [Full Text] [PDF]

				Z. Han, E. A. Hendrickson, T. A. Bremner, and J. H. Wyche A Sequential Two-Step Mechanism for the Production of the Mature p17:p12 Form of Caspase-3 in Vitro J. Biol. Chem., May 16, 1997; 272(20): 13432 - 13436. [Abstract] [Full Text] [PDF]

				M. Amling, L. Neff, S. Tanaka, D. Inoue, K. Kuida, E. Weir, W. M. Philbrick, A. E. Broadus, and R. Baron Bcl-2 Lies Downstream of Parathyroid Hormone-related Peptide in a Signaling Pathway That Regulates Chondrocyte Maturation during Skeletal Development J. Cell Biol., January 13, 1997; 136(1): 205 - 213. [Abstract] [Full Text] [PDF]

				Z. Han, N. Malik, T. Carter, W. H. Reeves, J. H. Wyche, and E. A. Hendrickson DNA-dependent Protein Kinase Is a Target for a CPP32-like Apoptotic Protease J. Biol. Chem., October 4, 1996; 271(40): 25035 - 25040. [Abstract] [Full Text] [PDF]

				Z. Han, C. Johnston, W. H. Reeves, T. Carter, J. H. Wyche, and E. A. Hendrickson Characterization of a Ku86 Variant Protein That Results in Altered DNA Binding and Diminished DNA-dependent Protein Kinase Activity J. Biol. Chem., June 14, 1996; 271(24): 14098 - 14104. [Abstract] [Full Text] [PDF]