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Specific Proteolytic Cleavage of Poly(ADP-ribose) Polymerase: An Early Marker of Chemotherapy-induced Apoptosis¹

The Oncology Center, Johns Hopkins Hospital (S. H. K., Y. O., N. E. D.), and Department of Pharmacology (S. H. K.), The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, and Poly(ADP-Ribose) Metabolism Group, Department of Molecular Endocrinology, Centre Hospitalier de l'Université Laval Research Center and Laval University (S. D., G. G. P.), Sainte-Foy, Quebec, Canada GIV 4G2

Apoptosis is a morphologically and biochemically distinct form of cell death that occurs under a variety of physiological and pathological conditions. In the present study, the proteolytic cleavage of poly(ADP-ribose) polymerase (pADPRp) during the course of chemotherapy-induced apoptosis was examined. Treatment of HL-60 human leukemia cells with the topoisomerase II-directed anticancer agent etoposide resulted in morphological changes characteristic of apoptosis. Endonucleolytic degradation of DNA to generate nucleosomal fragments occurred simultaneously. Western blotting with epitope-specific monoclonal and polyclonal antibodies revealed that these characteristic apoptotic changes were accompanied by early, quantitative cleavage of the M_r 116,000 pADPRp polypeptide to an M_r 25,000 fragment containing the amino-terminal DNA-binding domain of pADPRp and an M_r 85,000 fragment containing the automodification and catalytic domains. Activity blotting revealed that the M_r 85,000 fragment retained basal pADPRp activity but was not activated by exogenous nicked DNA. Similar cleavage of pADPRp was observed after exposure of HL-60 cells to a variety of chemotherapeutic agents including cis-diaminedichloroplatinum (II), colcemid, 1-ß-D-arabinofuranosylcytosine, and methotrexate; to -irradiation; or to the protein synthesis inhibitors puromycin or cycloheximide. Similar changes were observed in MDA-MB-468 human breast cancer cells treated with trifluorothymidine or 5-fluoro-2'-deoxyuridine and in -irradiated or glucocorticoid-treated rat thymocytes undergoing apoptosis. Treatment with several compounds (tosyl-L-lysine chloromethyl ketone, tosyl-L-phenylalanine chloromethyl ketone, N-ethylmaleimide, iodoacetamide) prevented both the proteolytic cleavage of pADPRp and the internucleosomal fragmentation of DNA. The results suggest that proteolytic cleavage of pADPRp, in addition to being an early marker of chemotherapy-induced apoptosis, might reflect more widespread proteolysis that is a critical biochemical event early during the process of physiological cell death.

¹ Supported in part by grants from the NIH (CA50435, CA55642, CA57545), Canadian Medical Research Council (MT6128), and Natural Sciences and Engineering Research Council of Canada (AO415). S. H. K. was supported by a Clinical Oncology Career Development Award from the American Cancer Society. S. D. received a predoctoral fellowship from the Fonds pour la Formation de Chercheurs et l'Aide à la Recherche. Y. O. was supported by a Stetler Research Fund fellowship.

² To whom reprint requests should be addressed, at Oncology 1-127, Johns Hopkins Hospital, 600 N. Wolfe Street, Baltimore, MD 21287.

Received 3/ 3/93. Accepted 6/21/93.

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				M. C. Marchetti, B. Di Marco, G. Cifone, G. Migliorati, and C. Riccardi Dexamethasone-induced apoptosis of thymocytes: role of glucocorticoid receptor-associated Src kinase and caspase-8 activation Blood, January 15, 2003; 101(2): 585 - 593. [Abstract] [Full Text] [PDF]

				C. Agarwal, R. P. Singh, and R. Agarwal Grape seed extract induces apoptotic death of human prostate carcinoma DU145 cells via caspases activation accompanied by dissipation of mitochondrial membrane potential and cytochrome c release Carcinogenesis, November 1, 2002; 23(11): 1869 - 1876. [Abstract] [Full Text] [PDF]

				K. Kabsch and A. Alonso The Human Papillomavirus Type 16 E5 Protein Impairs TRAIL- and FasL-Mediated Apoptosis in HaCaT Cells by Different Mechanisms J. Virol., October 25, 2002; 76(23): 12162 - 12172. [Abstract] [Full Text] [PDF]

				A. Benchoua, C. Couriaud, C. Guegan, L. Tartier, P. Couvert, G. Friocourt, J. Chelly, J. Menissier-de Murcia, and B. Onteniente Active Caspase-8 Translocates into the Nucleus of Apoptotic Cells to Inactivate Poly(ADP-ribose) Polymerase-2 J. Biol. Chem., September 6, 2002; 277(37): 34217 - 34222. [Abstract] [Full Text] [PDF]

				L. Virag and C. Szabo The Therapeutic Potential of Poly(ADP-Ribose) Polymerase Inhibitors Pharmacol. Rev., September 1, 2002; 54(3): 375 - 429. [Abstract] [Full Text] [PDF]

				A. Rachlis, J. L. Watson, J. Lu, and D. M. McKay Nitric oxide reduces bacterial superantigen-immune cell activation and consequent epithelial abnormalities J. Leukoc. Biol., August 1, 2002; 72(2): 339 - 346. [Abstract] [Full Text] [PDF]

				J. Ribera, V. Ayala, and J. E. Esquerda c-Jun-like Immunoreactivity in Apoptosis Is the Result of a Crossreaction with Neoantigenic Sites Exposed by Caspase-3-mediated Proteolysis J. Histochem. Cytochem., July 1, 2002; 50(7): 961 - 972. [Abstract] [Full Text]

				P. K. Baker, A. R. Pettitt, J. R. Slupsky, H. J. Chen, M. A. Glenn, M. Zuzel, and J. C. Cawley Response of hairy cells to IFN-alpha involves induction of apoptosis through autocrine TNF-alpha and protection by adhesion Blood, June 28, 2002; 100(2): 647 - 653. [Abstract] [Full Text] [PDF]

				D. F. Dukers, C. J. L. M. Meijer, R. L. ten Berge, W. Vos, G. J. Ossenkoppele, and J. J. Oudejans High numbers of active caspase 3-positive Reed-Sternberg cells in pretreatment biopsy specimens of patients with Hodgkin disease predict favorable clinical outcome Blood, June 17, 2002; 100(1): 36 - 42. [Abstract] [Full Text] [PDF]

				R.-L. Kuo, S.-H. Kung, Y.-Y. Hsu, and W.-T. Liu Infection with enterovirus 71 or expression of its 2A protease induces apoptotic cell death J. Gen. Virol., June 1, 2002; 83(6): 1367 - 1376. [Abstract] [Full Text] [PDF]

				D. D'Amours, F. R. Sallmann, V. M. Dixit, and G. G. Poirier Gain-of-function of poly(ADP-ribose) polymerase-1 upon cleavage by apoptotic proteases: implications for apoptosis J. Cell Sci., March 12, 2002; 114(20): 3771 - 3778. [Abstract] [Full Text] [PDF]

				M. Fujino, X.-K. Li, Y. Kitazawa, L. Guo, M. Kawasaki, N. Funeshima, T. Amano, and S. Suzuki Distinct Pathways of Apoptosis Triggered by FTY720, Etoposide, and Anti-Fas Antibody in Human T-Lymphoma Cell Line (Jurkat Cells) J. Pharmacol. Exp. Ther., March 1, 2002; 300(3): 939 - 945. [Abstract] [Full Text] [PDF]

				M. Los, M. Mozoluk, D. Ferrari, A. Stepczynska, C. Stroh, A. Renz, Z. Herceg, Z.-Q. Wang, and K. Schulze-Osthoff Activation and Caspase-mediated Inhibition of PARP: A Molecular Switch between Fibroblast Necrosis and Apoptosis in Death Receptor Signaling Mol. Biol. Cell, March 1, 2002; 13(3): 978 - 988. [Abstract] [Full Text] [PDF]

				M. Uchida, S. Hanai, N. Uematsu, K. Sawamoto, H. Okano, M. Miwa, and K. Uchida Overexpression of Poly(ADP-ribose) Polymerase Disrupts Organization of Cytoskeletal F-actin and Tissue Polarity in Drosophila J. Biol. Chem., February 15, 2002; 277(8): 6696 - 6702. [Abstract] [Full Text] [PDF]

				A. C. Boyonoski, J. C. Spronck, L. M. Gallacher, R. M. Jacobs, G. M. Shah, G. G. Poirier, and J. B. Kirkland Niacin Deficiency Decreases Bone Marrow Poly(ADP-Ribose) and the Latency of Ethylnitrosourea-Induced Carcinogenesis in Rats J. Nutr., January 1, 2002; 132(1): 108 - 114. [Abstract] [Full Text] [PDF]

				A. C. Boyonoski, J. C. Spronck, R. M. Jacobs, G. M. Shah, G. G. Poirier, and J. B. Kirkland Pharmacological Intakes of Niacin Increase Bone Marrow Poly(ADP-Ribose) and the Latency of Ethylnitrosourea-Induced Carcinogenesis in Rats J. Nutr., January 1, 2002; 132(1): 115 - 120. [Abstract] [Full Text] [PDF]

				Y. Tong, Q. Yang, C. Vater, L.K. Venkatesh, D. Custeau, T. Chittenden, G. Chinnadurai, and H. Gourdeau The Pro-apoptotic Protein, Bik, Exhibits Potent Antitumor Activity That Is Dependent on Its BH3 Domain Mol. Cancer Ther., December 1, 2001; 1(2): 95 - 102. [Abstract] [Full Text] [PDF]

				E. U. Kurz, S. E. Wilson, K. B. Leader, B. P. Sampey, W. P. Allan, J. C. Yalowich, and D. J. Kroll The Histone Deacetylase Inhibitor Sodium Butyrate Induces DNA Topoisomerase II{alpha} Expression and Confers Hypersensitivity to Etoposide in Human Leukemic Cell Lines Mol. Cancer Ther., December 1, 2001; 1(2): 121 - 131. [Abstract] [Full Text] [PDF]

				D. T. Jones, K. Ganeshaguru, A. E. Virchis, N. I. Folarin, M. W. Lowdell, A. B. Mehta, H. G. Prentice, A. V. Hoffbrand, and R. G. Wickremasinghe Caspase 8 activation independent of Fas (CD95/APO-1) signaling may mediate killing of B-chronic lymphocytic leukemia cells by cytotoxic drugs or gamma radiation Blood, November 1, 2001; 98(9): 2800 - 2807. [Abstract] [Full Text] [PDF]

				Z. Han, P. Pantazis, J. H. Wyche, N. Kouttab, V. J. Kidd, and E. A. Hendrickson A Fas-associated Death Domain Protein-dependent Mechanism Mediates the Apoptotic Action of Non-steroidal Anti-inflammatory Drugs in the Human Leukemic Jurkat Cell Line J. Biol. Chem., October 12, 2001; 276(42): 38748 - 38754. [Abstract] [Full Text] [PDF]

				S. Chatterjee, K. H. Brite, and A. Matsumura Induction of Apoptosis of Integrin-expressing Human Prostate Cancer Cells by Cyclic Arg-Gly-Asp Peptides Clin. Cancer Res., October 1, 2001; 7(10): 3006 - 3011. [Abstract] [Full Text] [PDF]

				Y. Ito, P. Pandey, N. Mishra, S. Kumar, N. Narula, S. Kharbanda, S. Saxena, and D. Kufe Targeting of the c-Abl Tyrosine Kinase to Mitochondria in Endoplasmic Reticulum Stress-Induced Apoptosis Mol. Cell. Biol., September 15, 2001; 21(18): 6233 - 6242. [Abstract] [Full Text] [PDF]

				S. Sengupta and B. Wasylyk Ligand-dependent interaction of the glucocorticoid receptor with p53 enhances their degradation by Hdm2 Genes & Dev., September 15, 2001; 15(18): 2367 - 2380. [Abstract] [Full Text] [PDF]

				A. Senchenkov, T.-Y. Han, H. Wang, A. E. Frankel, T. J. Kottke, S. H. Kaufmann, and M. C. Cabot Enhanced ceramide generation and induction of apoptosis in human leukemia cells exposed to DT388-granulocyte-macrophage colony-stimulating factor (GM-CSF), a truncated diphtheria toxin fused to human GM-CSF Blood, September 15, 2001; 98(6): 1927 - 1934. [Abstract] [Full Text] [PDF]