Journal of Clinical Oncology, Vol 17, Issue 9
(September), 1999: 2941
© 1999 American Society for Clinical Oncology
Dysregulation of Apoptosis in Cancer
John C. Reed
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/hormoneindependent 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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P. K. M. Kim, S.-Y. Park, P. P. Koty, Y. Hua, J. D. Luketich, and T. R. Billiar
Fas-associating death domain protein overexpression induces apoptosis in lung cancer cells
J. Thorac. Cardiovasc. Surg.,
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D. M. Gascoyne, R. M. Kypta, and M. d. M. Vivanco
Glucocorticoids Inhibit Apoptosis during Fibrosarcoma Development by Transcriptionally Activating Bcl-xL
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G. Tortora, R. Caputo, V. Damiano, R. Caputo, T. Troiani, B. M. Veneziani, S. De Placido, A. R. Bianco, U. Zangemeister-Wittke, and F. Ciardiello
Combined Targeted Inhibition of bcl-2, bcl-XL, Epidermal Growth Factor Receptor, and Protein Kinase A Type I Causes Potent Antitumor, Apoptotic, and Antiangiogenic Activity
Clin. Cancer Res.,
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G. Marcucci, J. C. Byrd, G. Dai, M. I. Klisovic, P. J. Kourlas, D. C. Young, S. R. Cataland, D. B. Fisher, D. Lucas, K. K. Chan, et al.
Phase 1 and pharmacodynamic studies of G3139, a Bcl-2 antisense oligonucleotide, in combination with chemotherapy in refractory or relapsed acute leukemia
Blood,
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M. Holcik, B. W. Gordon, and R. G. Korneluk
The Internal Ribosome Entry Site-Mediated Translation of Antiapoptotic Protein XIAP Is Modulated by the Heterogeneous Nuclear Ribonucleoproteins C1 and C2
Mol. Cell. Biol.,
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M.-F. Demierre and L. Nathanson
Chemoprevention of Melanoma: An Unexplored Strategy
J. Clin. Oncol.,
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D. R. Mercatante, J. L. Mohler, and R. Kole
Cellular Response to an Antisense-mediated Shift of Bcl-x Pre-mRNA Splicing and Antineoplastic Agents
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T. Yamada, M. Goto, V. Punj, O. Zaborina, K. Kimbara, T. K. Das Gupta, and A. M. Chakrabarty
The Bacterial Redox Protein Azurin Induces Apoptosis in J774 Macrophages through Complex Formation and Stabilization of the Tumor Suppressor Protein p53
Infect. Immun.,
December 1, 2002;
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T. Yamada, M. Goto, V. Punj, O. Zaborina, M. L. Chen, K. Kimbara, D. Majumdar, E. Cunningham, T. K. Das Gupta, and A. M. Chakrabarty
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PNAS,
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J. Chen, A. Freeman, J. Liu, Q. Dai, and R.-m. Lee
The Apoptotic Effect of HA14-1, a Bcl-2-interacting Small Molecular Compound, Requires Bax Translocation and Is Enhanced by PK11195
Mol. Cancer Ther.,
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M. Spies, V. L. Chappell, M. R. Dasu, D. N. Herndon, J. C. Thompson, and S. E. Wolf
Role of TNF-alpha in gut mucosal changes after severe burn
Am J Physiol Gastrointest Liver Physiol,
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M. G. Sanna, J. da Silva Correia, Y. Luo, B. Chuang, L. M. Paulson, B. Nguyen, Q. L. Deveraux, and R. J. Ulevitch
ILPIP, a Novel Anti-apoptotic Protein That Enhances XIAP-mediated Activation of JNK1 and Protection against Apoptosis
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C. G. Ferreira, M. Epping, F. A. E. Kruyt, and G. Giaccone
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P. Theodorakis, E. Lomonosova, and G. Chinnadurai
Critical Requirement of BAX for Manifestation of Apoptosis Induced by Multiple Stimuli in Human Epithelial Cancer Cells
Cancer Res.,
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S. Gorski and M. Marra
Programmed cell death takes flight: genetic and genomic approaches to gene discovery in Drosophila
Physiol Genomics,
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C. M. Barrett, F. L. Lewis, J. B. Roaten, T. W. Sweatman, M. Israel, J. L. Cleveland, and L. Lothstein
Novel Extranuclear-targeted Anthracyclines Override the Antiapoptotic Functions of Bcl-2 and Target Protein Kinase C Pathways to Induce Apoptosis
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F. Ciardiello and G. Tortora
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M. G. Sanna, J. d. S. Correia, O. Ducrey, J. Lee, K. Nomoto, N. Schrantz, Q. L. Deveraux, and R. J. Ulevitch
IAP Suppression of Apoptosis Involves Distinct Mechanisms: the TAK1/JNK1 Signaling Cascade and Caspase Inhibition
Mol. Cell. Biol.,
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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
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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
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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,
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[Abstract]
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D. G. Stupack and D. A. Cheresh
Get a ligand, get a life: integrins, signaling and cell survival
J. Cell Sci.,
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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
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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,
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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
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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.,
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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
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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,
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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
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M. Parton, M. Dowsett, and I. Smith
Studies of apoptosis in breast cancer
BMJ,
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M. V. Blagosklonny and A. B. Pardee
Exploiting Cancer Cell Cycling for Selective Protection of Normal Cells
Cancer Res.,
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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
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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
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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,
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D. Grossman, P. J. Kim, J. S. Schechner, and D. C. Altieri
Inhibition of melanoma tumor growth in vivo by survivin targeting
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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
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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
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S. A. Cannistra
When Is a ""Prognostic Factor"" Really Prognostic?
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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
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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
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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
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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
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