Cell Growth & Differentiation, Vol 6, Issue 4 363-370, Copyright © 1995 by American Association of Cancer Research

ARTICLES

Overexpression of Bcl-XL by cytotoxic drug exposure confers resistance to ionizing radiation-induced internucleosomal DNA fragmentation

R Datta, Y Manome, N Taneja, LH Boise, R Weichselbaum, CB Thompson, CA Slapak and D Kufe
Division of Cancer Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.

Acquired resistance to diverse chemotherapeutic agents has been associated with overexpression of the P-glycoprotein. We have selected human U-937 cells for clones resistant to the cytotoxic agents doxorubicin (U-A20) and vincristine (U-V20). The results demonstrate that P-glycoprotein-positive U-A20 and U-V20 cells exhibit resistance to inducers of internucleosomal DNA fragmentation. Although parental U-937 cells responded to ionizing radiation with the DNA laddering characteristic of physiological cell death, the drug-resistant lines were insensitive to this effect. The U-A20 and U-V20 clones were also resistant to endonucleolytic DNA cleavage associated with exposure to tumor necrosis factor or ceramide. Previous work has demonstrated that physiological cell death is inhibited by overexpression of the Bcl-2 protein. However, analysis of Bcl-2 revealed similar levels in the parental and drug-resistant cells. In contrast, we show that U-A20 and U-V20 cells overexpress the Bcl-2-related protein, Bcl-xL. Moreover, studies with a U-937 cell line transfected with a Bcl-XL expression vector confirm resistance to ionizing radiation-induced DNA fragmentation and cell killing. These findings suggest that, unlike Bcl-2, Bcl-XL may be constitutively overexpressed as a result of selection for cytotoxic drug resistance and that Bcl-XL participates in an acquired form of multimodality resistance to chemotherapeutic agents and radiation.

This article has been cited by other articles:

				D. Raina, S. Kharbanda, and D. Kufe The MUC1 Oncoprotein Activates the Anti-apoptotic Phosphoinositide 3-Kinase/Akt and Bcl-xL Pathways in Rat 3Y1 Fibroblasts J. Biol. Chem., May 14, 2004; 279(20): 20607 - 20612. [Abstract] [Full Text] [PDF]

				T. Ikeda, M. Sporn, T. Honda, G. W. Gribble, and D. Kufe The Novel Triterpenoid CDDO and its Derivatives Induce Apoptosis by Disruption of Intracellular Redox Balance Cancer Res., September 1, 2003; 63(17): 5551 - 5558. [Abstract] [Full Text] [PDF]

				G. Acs, P. J. Zhang, C. M. McGrath, P. Acs, J. McBroom, A. Mohyeldin, S. Liu, H. Lu, and A. Verma Hypoxia-Inducible Erythropoietin Signaling in Squamous Dysplasia and Squamous Cell Carcinoma of the Uterine Cervix and Its Potential Role in Cervical Carcinogenesis and Tumor Progression Am. J. Pathol., June 1, 2003; 162(6): 1789 - 1806. [Abstract] [Full Text] [PDF]

				E. Davila, M. G. Velez, C. J. Heppelmann, and E. Celis Creating space: an antigen-independent, CpG-induced peripheral expansion of naive and memory T lymphocytes in a full T-cell compartment Blood, September 18, 2002; 100(7): 2537 - 2545. [Abstract] [Full Text] [PDF]

				S. Mabuchi, M. Ohmichi, A. Kimura, K. Hisamoto, J. Hayakawa, Y. Nishio, K. Adachi, K. Takahashi, E. Arimoto-Ishida, Y. Nakatsuji, et al. Inhibition of Phosphorylation of BAD and Raf-1 by Akt Sensitizes Human Ovarian Cancer Cells to Paclitaxel J. Biol. Chem., August 30, 2002; 277(36): 33490 - 33500. [Abstract] [Full Text] [PDF]

				H. Kojima, M. Iida, H. Miyazaki, T. Koga, H. Moriyama, and Y. Manome Enhancement of Cytarabine Sensitivity in Squamous Cell Carcinoma Cell Line Transfected With Deoxycytidine Kinase Arch Otolaryngol Head Neck Surg, June 1, 2002; 128(6): 708 - 713. [Abstract] [Full Text] [PDF]

				K. Yoshida, K. Komatsu, H.-G. Wang, and D. Kufe c-Abl Tyrosine Kinase Regulates the Human Rad9 Checkpoint Protein in Response to DNA Damage Mol. Cell. Biol., May 15, 2002; 22(10): 3292 - 3300. [Abstract] [Full Text] [PDF]

				K. Yoshida and D. Kufe Negative Regulation of the SHPTP1 Protein Tyrosine Phosphatase by Protein Kinase C delta in Response to DNA Damage Mol. Pharmacol., December 1, 2001; 60(6): 1431 - 1438. [Abstract] [Full Text] [PDF]

				M. A. Shah and G. K. Schwartz Cell Cycle-mediated Drug Resistance: An Emerging Concept in Cancer Therapy Clin. Cancer Res., August 1, 2001; 7(8): 2168 - 2181. [Abstract] [Full Text] [PDF]

				J.-P. JAFFREZOU, A. P. BRUNO, A. MOISAND, T. LEVADE, and G. LAURENT Activation of a nuclear sphingomyelinase in radiation-induced apoptosis FASEB J, January 1, 2001; 15(1): 123 - 133. [Abstract] [Full Text] [PDF]

				C. Nicot, R. Mahieux, S. Takemoto, and G. Franchini Bcl-XL is up-regulated by HTLV-I and HTLV-II in vitro and in ex vivo ATLL samples Blood, July 1, 2000; 96(1): 275 - 281. [Abstract] [Full Text] [PDF]

				Y. Ito, P. Pandey, A. Place, M. B. Sporn, G. W. Gribble, T. Honda, S. Kharbanda, and D. Kufe The Novel Triterpenoid 2-Cyano-3,12-dioxoolean-1,9-dien-28-oic Acid Induces Apoptosis of Human Myeloid Leukemia Cells by a Caspase-8-dependent Mechanism Cell Growth Differ., May 1, 2000; 11(5): 261 - 267. [Abstract] [Full Text]

				S. J. Chmura, E. Nodzenski, S. Kharbanda, P. Pandey, J. Quintans, D. W. Kufe, and R. R. Weichselbaum Down-Regulation of Ceramide Production Abrogates Ionizing Radiation-Induced Cytochrome c Release and Apoptosis Mol. Pharmacol., April 1, 2000; 57(4): 792 - 796. [Abstract] [Full Text]

				S. Kharbanda, S. Saxena, K. Yoshida, P. Pandey, M. Kaneki, Q. Wang, K. Cheng, Y.-N. Chen, A. Campbell, T. Sudha, et al. Translocation of SAPK/JNK to Mitochondria and Interaction with Bcl-xL in Response to DNA Damage J. Biol. Chem., January 7, 2000; 275(1): 322 - 327. [Abstract] [Full Text] [PDF]

				R. Liu, C. Page, D. R. Beidler, M. S. Wicha, and G. Nunez Overexpression of Bcl-xL Promotes Chemotherapy Resistance of Mammary Tumors in a Syngeneic Mouse Model Am. J. Pathol., December 1, 1999; 155(6): 1861 - 1867. [Abstract] [Full Text] [PDF]

				H. Kojima, H. Miyazaki, Y. Tanaka, M. Shiwa, T. Koga, and H. Moriyama Role of Bcl-xL Protein in Differentiation and Apoptosis of Human Middle Ear Cholesteatoma Epithelium Arch Otolaryngol Head Neck Surg, July 1, 1999; 125(7): 738 - 742. [Abstract] [Full Text] [PDF]

				S. J. Advani, S.-M. Chung, S. Y. Yan, G. Y. Gillespie, J. M. Markert, R. J. Whitley, B. Roizman, and R. R. Weichselbaum Replication-competent, Nonneuroinvasive Genetically Engineered Herpes Virus Is Highly Effective in the Treatment of Therapy-resistant Experimental Human Tumors Cancer Res., May 1, 1999; 59(9): 2055 - 2058. [Abstract] [Full Text] [PDF]

				P. Pandey, S. Avraham, A. Place, V. Kumar, P. K. Majumder, K. Cheng, A. Nakazawa, S. Saxena, and S. Kharbanda Bcl-xL Blocks Activation of Related Adhesion Focal Tyrosine Kinase/Proline-rich Tyrosine Kinase 2 and Stress-activated Protein Kinase/c-Jun N-terminal Protein Kinase in the Cellular Response to Methylmethane Sulfonate J. Biol. Chem., March 26, 1999; 274(13): 8618 - 8623. [Abstract] [Full Text] [PDF]

				T. Gumienny, E Lambie, E Hartwieg, H. Horvitz, and M. Hengartner Genetic control of programmed cell death in the Caenorhabditis elegans hermaphrodite germline Development, January 2, 1999; 126(5): 1011 - 1022. [Abstract] [PDF]

				M. Kaneki, S. Kharbanda, P. Pandey, K. Yoshida, M. Takekawa, J.-R. Liou, R. Stone, and D. Kufe Functional Role for Protein Kinase Cbeta as a Regulator of Stress-Activated Protein Kinase Activation and Monocytic Differentiation of Myeloid Leukemia Cells Mol. Cell. Biol., January 1, 1999; 19(1): 461 - 470. [Abstract] [Full Text] [PDF]

				H. Kojima, K. Endo, H. Moriyama, Y. Tanaka, E. S. Alnemri, C. A. Slapak, B. Teicher, D. Kufe, and R. Datta Abrogation of Mitochondrial Cytochrome c Release and Caspase-3 Activation in Acquired Multidrug Resistance J. Biol. Chem., July 3, 1998; 273(27): 16647 - 16650. [Abstract] [Full Text] [PDF]

				G. P. Amarante-Mendes, C. Naekyung Kim, L. Liu, Y. Huang, C. L. Perkins, D. R. Green, and K. Bhalla Bcr-Abl Exerts Its Antiapoptotic Effect Against Diverse Apoptotic Stimuli Through Blockage of Mitochondrial Release of Cytochrome C and Activation of Caspase-3 Blood, March 1, 1998; 91(5): 1700 - 1705. [Abstract] [Full Text] [PDF]

				S. H. Kaufmann, J. E. Karp, P. A. Svingen, S. Krajewski, P. J. Burke, S. D. Gore, and J. C. Reed Elevated Expression of the Apoptotic Regulator Mcl-1 at the Time of Leukemic Relapse Blood, February 1, 1998; 91(3): 991 - 1000. [Abstract] [Full Text] [PDF]

				R. Datta, H. Kojima, K. Yoshida, and D. Kufe Caspase-3-mediated Cleavage of Protein Kinase C theta  in Induction of Apoptosis J. Biol. Chem., August 15, 1997; 272(33): 20317 - 20320. [Abstract] [Full Text] [PDF]

				S. Kharbanda, P. Pandey, L. Schofield, S. Israels, R. Roncinske, K. Yoshida, A. Bharti, Z.-M. Yuan, S. Saxena, R. Weichselbaum, et al. Role for Bcl-xL as an inhibitor of cytosolic cytochrome C accumulation in DNA damage-induced apoptosis PNAS, June 24, 1997; 94(13): 6939 - 6942. [Abstract] [Full Text] [PDF]

				H. W. Findley, L. Gu, A. M. Yeager, and M. Zhou Expression and Regulation of Bcl-2, Bcl-xl, and Bax Correlate With p53 Status and Sensitivity to Apoptosis in Childhood Acute Lymphoblastic Leukemia Blood, April 15, 1997; 89(8): 2986 - 2993. [Abstract] [Full Text] [PDF]

				R. Datta, H. Kojima, D. Banach, N. J. Bump, R. V. Talanian, E. S. Alnemri, R. R. Weichselbaum, W. W. Wong, and D. W. Kufe Activation of a CrmA-insensitive, p35-sensitive Pathway in Ionizing Radiation-induced Apoptosis J. Biol. Chem., January 17, 1997; 272(3): 1965 - 1969. [Abstract] [Full Text] [PDF]

				P. Erhardt and G. M. Cooper Activation of the CPP32 Apoptotic Protease by Distinct Signaling Pathways with Differential Sensitivity to Bcl-xL J. Biol. Chem., July 26, 1996; 271(30): 17601 - 17604. [Abstract] [Full Text] [PDF]

				K. Endo, E. Oki, V. Biedermann, H. Kojima, K. Yoshida, F.-J. Johannes, D. Kufe, and R. Datta Proteolytic Cleavage and Activation of Protein Kinase C {micro} by Caspase-3 in the Apoptotic Response of Cells to 1-beta -D-Arabinofuranosylcytosine and Other Genotoxic Agents J. Biol. Chem., June 9, 2000; 275(24): 18476 - 18481. [Abstract] [Full Text] [PDF]

				R. Datta, E. Oki, K. Endo, V. Biedermann, J. Ren, and D. Kufe XIAP Regulates DNA Damage-induced Apoptosis Downstream of Caspase-9 Cleavage J. Biol. Chem., October 6, 2000; 275(41): 31733 - 31738. [Abstract] [Full Text] [PDF]