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Dysregulation of Apoptosis in Cancer

From the The Burnham Institute, La Jolla, CA.

Address reprint requests to John C. Reed, MD, PhD, The Burnham Institute, 10901 North Torrey Pines Rd, La Jolla, CA 92037

ABSTRACT

ABSTRACT: Each day, approximately 50 to 70 billion cells perish in the average adult because of programmed cell death (PCD). Cell death in self-renewing tissues, such as the skin, gut, and bone marrow, is necessary to make room for the billions of new cells produced daily. So massive is the flux of cells through our bodies that, in a typical year, each of us will produce and, in parallel, eradicate a mass of cells equal to almost our entire body weight. The morphologic ritual cells go through when experiencing PCD has been termed apoptosis and is executed by a family of intracellular proteases, called caspases. Unlike accidental cell deaths caused by infarction and trauma, these physiologic deaths culminate in fragmentation of cells into membrane-encased bodies which are cleared through phagocytosis by neighboring cells without inciting inflammatory reactions or tissue scarring. Defects in the processes controlling PCD can extend cell life span, contributing to neoplastic cell expansion independently of cell division. Moreover, failures in normal apoptosis pathways contribute to carcinogenesis by creating a permissive environment for genetic instability and accumulation of gene mutations, promoting resistance to immune-based destruction, allowing disobeyance of cell cycle checkpoints that would normally induce apoptosis, facilitating growth factor/hormone–independent cell survival, supporting anchorage-independent survival during metastasis, reducing dependence on oxygen and nutrients, and conferring resistance to cytotoxic anticancer drugs and radiation. Elucidation of the genes that constitute the core machinery of the cell death pathway has provided new insights into tumor biology, revealing novel strategies for combating cancer.

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				M. J. Morris, W. P. Tong, C. Cordon-Cardo, M. Drobnjak, W. K. Kelly, S. F. Slovin, K. L. Terry, K. Siedlecki, P. Swanson, M. Rafi, et al. Phase I Trial of BCL-2 Antisense Oligonucleotide (G3139) Administered by Continuous Intravenous Infusion in Patients with Advanced Cancer Clin. Cancer Res., March 1, 2002; 8(3): 679 - 683. [Abstract] [Full Text] [PDF]

				A. Y. Xiao, L. Wei, S. Xia, S. Rothman, and S. P. Yu Ionic Mechanism of Ouabain-Induced Concurrent Apoptosis and Necrosis in Individual Cultured Cortical Neurons J. Neurosci., February 15, 2002; 22(4): 1350 - 1362. [Abstract] [Full Text] [PDF]

				J. C. Byrd, S. Kitada, I. W. Flinn, J. L. Aron, M. Pearson, D. Lucas, and J. C. Reed The mechanism of tumor cell clearance by rituximab in vivo in patients with B-cell chronic lymphocytic leukemia: evidence of caspase activation and apoptosis induction Blood, February 1, 2002; 99(3): 1038 - 1043. [Abstract] [Full Text] [PDF]

				D. G. Stupack and D. A. Cheresh Get a ligand, get a life: integrins, signaling and cell survival J. Cell Sci., January 10, 2002; 115(19): 3729 - 3738. [Abstract] [Full Text] [PDF]

				P. Kozuch, M. L. Grossbard, A. Barzdins, M. Araneo, A. Robin, D. Frager, P. Homel, J. Marino, P. DeGregorio, and H.W. Bruckner Irinotecan Combined with Gemcitabine, 5-Fluorouracil, Leucovorin, and Cisplatin (G-FLIP) is an Effective and Noncrossresistant Treatment for Chemotherapy Refractory Metastatic Pancreatic Cancer Oncologist, December 1, 2001; 6(6): 488 - 495. [Abstract] [Full Text] [PDF]

				J. R. Kanwar, W.-P. Shen, R. K. Kanwar, R. W. Berg, and G. W. Krissansen Effects of Survivin Antagonists on Growth of Established Tumors and B7-1 Immunogene Therapy J Natl Cancer Inst, October 17, 2001; 93(20): 1541 - 1552. [Abstract] [Full Text] [PDF]

				S. S. Martin and P. Leder Human MCF10A Mammary Epithelial Cells Undergo Apoptosis following Actin Depolymerization That Is Independent of Attachment and Rescued by Bcl-2 Mol. Cell. Biol., October 1, 2001; 21(19): 6529 - 6536. [Abstract] [Full Text] [PDF]

				V. M. Dirsch, H. Stuppner, and A. M. Vollmar Helenalin Triggers a CD95 Death Receptor-independent Apoptosis That Is Not Affected by Overexpression of Bcl-xL or Bcl-2 Cancer Res., August 1, 2001; 61(15): 5817 - 5823. [Abstract] [Full Text] [PDF]

				G. Tortora, R. Caputo, V. Damiano, R. Bianco, G. Fontanini, S. Cuccato, S. De Placido, A. R. Bianco, and F. Ciardiello Combined Blockade of Protein Kinase A and Bcl-2 by Antisense Strategy Induces Apoptosis and Inhibits Tumor Growth and Angiogenesis Clin. Cancer Res., August 1, 2001; 7(8): 2537 - 2544. [Abstract] [Full Text] [PDF]

				J. M. Grad, N. J. Bahlis, I. Reis, M. M. Oshiro, W. S. Dalton, and L. H. Boise Ascorbic acid enhances arsenic trioxide-induced cytotoxicity in multiple myeloma cells Blood, August 1, 2001; 98(3): 805 - 813. [Abstract] [Full Text] [PDF]

				E. L. Soucie, M. G. Annis, J. Sedivy, J. Filmus, B. Leber, D. W. Andrews, and L. Z. Penn Myc Potentiates Apoptosis by Stimulating Bax Activity at the Mitochondria Mol. Cell. Biol., July 15, 2001; 21(14): 4725 - 4736. [Abstract] [Full Text] [PDF]

				M. Parton, M. Dowsett, and I. Smith Studies of apoptosis in breast cancer BMJ, June 23, 2001; 322(7301): 1528 - 1532. [Full Text] [PDF]

				M. V. Blagosklonny and A. B. Pardee Exploiting Cancer Cell Cycling for Selective Protection of Normal Cells Cancer Res., June 1, 2001; 61(11): 4301 - 4305. [Abstract] [Full Text] [PDF]

				M. Mesri, M. Morales-Ruiz, E. J. Ackermann, C. F. Bennett, J. S. Pober, W. C. Sessa, and D. C. Altieri Suppression of Vascular Endothelial Growth Factor-Mediated Endothelial Cell Protection by Survivin Targeting Am. J. Pathol., May 1, 2001; 158(5): 1757 - 1765. [Abstract] [Full Text] [PDF]

				H. Ishii, K. R. Dumon, A. Vecchione, F. Trapasso, K. Mimori, H. Alder, M. Mori, G. Sozzi, R. Baffa, K. Huebner, et al. Effect of Adenoviral Transduction of the Fragile Histidine Triad Gene into Esophageal Cancer Cells Cancer Res., February 1, 2001; 61(4): 1578 - 1584. [Abstract] [Full Text]

				S. D. Smith, M. A. Wheeler, J. Plescia, J. W. Colberg, R. M. Weiss, and D. C. Altieri Urine Detection of Survivin and Diagnosis of Bladder Cancer JAMA, January 17, 2001; 285(3): 324 - 328. [Abstract] [Full Text] [PDF]

				D. Grossman, P. J. Kim, J. S. Schechner, and D. C. Altieri Inhibition of melanoma tumor growth in vivo by survivin targeting PNAS, January 5, 2001; (2001) 230450097. [Abstract] [Full Text]

				T Sourisseau, C Desbois, L Debure, D. Bowtell, A. Cato, J Schneikert, E Moyse, and D Michel Alteration of the stability of Bag-1 protein in the control of olfactory neuronal apoptosis J. Cell Sci., January 4, 2001; 114(7): 1409 - 1416. [Abstract] [PDF]

				S. Paglin, T. Hollister, T. Delohery, N. Hackett, M. McMahill, E. Sphicas, D. Domingo, and J. Yahalom A Novel Response of Cancer Cells to Radiation Involves Autophagy and Formation of Acidic Vesicles Cancer Res., January 1, 2001; 61(2): 439 - 444. [Abstract] [Full Text]

				S. A. Cannistra When Is a ""Prognostic Factor"" Really Prognostic? J. Clin. Oncol., November 15, 2000; 18(22): 3745 - 3747. [Full Text] [PDF]

				V. Rochat-Steiner, K. Becker, O. Micheau, P. Schneider, K. Burns, and J. Tschopp Fist/Hipk3: A FAS/Fadd-Interacting Serine/Threonine Kinase That Induces Fadd Phosphorylation and Inhibits FAS-Mediated Jun Nh2-Terminal Kinase Activation J. Exp. Med., October 16, 2000; 192(8): 1165 - 1174. [Abstract] [Full Text] [PDF]

				B. A. Wagner, G. R. Buettner, L. W. Oberley, C. J. Darby, and C. P. Burns Myeloperoxidase Is Involved in H2O2-induced Apoptosis of HL-60 Human Leukemia Cells J. Biol. Chem., July 14, 2000; 275(29): 22461 - 22469. [Abstract] [Full Text] [PDF]

				D. R. Mercatante, C. D. Bortner, J. A. Cidlowski, and R. Kole Modification of Alternative Splicing of Bcl-x Pre-mRNA in Prostate and Breast Cancer Cells. ANALYSIS OF APOPTOSIS AND CELL DEATH J. Biol. Chem., May 4, 2001; 276(19): 16411 - 16417. [Abstract] [Full Text] [PDF]

				E. Leo, Q. L. Deveraux, C. Buchholtz, K. Welsh, S.-i. Matsuzawa, H. R. Stennicke, G. S. Salvesen, and J. C. Reed TRAF1 Is a Substrate of Caspases Activated during Tumor Necrosis Factor Receptor-alpha -induced Apoptosis J. Biol. Chem., March 9, 2001; 276(11): 8087 - 8093. [Abstract] [Full Text] [PDF]