Transforming Growth Factor-β1 Induces Apoptosis through Fas Ligand-independent Activation of the Fas Death Pathway in Human Gastric SNU-620 Carcinoma Cells

To date, two major apoptotic pathways, the death receptor and the mitochondrial pathway, have been well documented in mammalian cells. However, the involvement of these two apoptotic pathways, particularly the death receptor pathway, in transforming growth factor-beta 1 (TGF-beta 1)-induced apoptosis is not well understood. Herein, we report that apoptosis of human gastric SNU-620 carcinoma cells induced by TGF-beta 1 is caused by the Fas death pathway in a Fas ligand-independent manner, and that the Fas death pathway activated by TGF-beta 1 is linked to the mitochondrial apoptotic pathway via Bid mediation. We showed that TGF-beta 1 induced the expression and activation of Fas and the subsequent caspase-8-mediated Bid cleavage. Interestingly, expression of dominant negative FADD and treatment with caspase-8 inhibitor efficiently prevented TGF-beta 1-induced apoptosis, whereas the treatment with an activating CH11 or a neutralizing ZB4 anti-Fas antibody, recombinant Fas ligand, or Fas-Fc chimera did not affect activation of Fas and the subsequent induction of apoptosis by TGF-beta 1. We further demonstrated that TGF-beta 1 also activates the mitochondrial pathway showing Bid-mediated loss of mitochondrial membrane potential and subsequent cytochrome c release associated with the activations of caspase-9 and the effector caspases. Moreover, all these apoptotic events induced by TGF-beta 1 were found to be effectively inhibited by Smad3 knockdown and also completely abrogated by Smad7 expression, suggesting the involvement of the Smad3 pathway upstream of the Fas death pathway by TGF-beta 1.

[1]  C. Heldin,et al.  Transforming growth factor-beta1 (TGF-beta)-induced apoptosis of prostate cancer cells involves Smad7-dependent activation of p38 by TGF-beta-activated kinase 1 and mitogen-activated protein kinase kinase 3. , 2003, Molecular biology of the cell.

[2]  C. Heldin,et al.  Mechanisms of TGF-beta signaling in regulation of cell growth and differentiation. , 2002, Immunology letters.

[3]  B. Calabretta,et al.  Transforming Growth Factor 1 Induces Apoptosis through Cleavage of BAD in a Smad3-Dependent Mechanism in FaO Hepatoma Cells , 2002 .

[4]  M. Bourgeade,et al.  p38-mediated regulation of an Fas-associated death domain protein-independent pathway leading to caspase-8 activation during TGFbeta-induced apoptosis in human Burkitt lymphoma B cells BL41. , 2001, Molecular biology of the cell.

[5]  E. Bottinger,et al.  Apoptosis in podocytes induced by TGF-β and Smad7 , 2001 .

[6]  Robert A. Weinberg,et al.  TGF-β-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation , 2001, Nature Cell Biology.

[7]  Sang Gyun Kim,et al.  Caspase-mediated Cdk2 activation is a critical step to execute transforming growth factor-β1-induced apoptosis in human gastric cancer cells , 2001, Oncogene.

[8]  F. Lallemand,et al.  Smad7 inhibits the survival nuclear factor κB and potentiates apoptosis in epithelial cells , 2001, Oncogene.

[9]  R. Derynck,et al.  Smad7 Is Induced by CD40 and Protects WEHI 231 B-lymphocytes from Transforming Growth Factor-β-induced Growth Inhibition and Apoptosis* , 2000, The Journal of Biological Chemistry.

[10]  H. Lodish,et al.  Critical Role of Smads and AP-1 Complex in Transforming Growth Factor-β-dependent Apoptosis* , 2000, The Journal of Biological Chemistry.

[11]  M. Hengartner.  The biochemistry of apoptosis , 2000, Nature.

[12]  A. Moustakas,et al.  Role of Smad Proteins and Transcription Factor Sp1 in p21Waf1/Cip1 Regulation by Transforming Growth Factor-β* , 2000, The Journal of Biological Chemistry.

[13]  Ester Piek,et al.  Role of Transforming Growth Factor-β Signaling in Cancer , 2000 .

[14]  Andrew V. Nguyen,et al.  Transforming growth factor beta3 induces cell death during the first stage of mammary gland involution. , 2000, Development.

[15]  R M Siegel,et al.  A domain in TNF receptors that mediates ligand-independent receptor assembly and signaling. , 2000, Science.

[16]  J K Frederiksen,et al.  Fas preassociation required for apoptosis signaling and dominant inhibition by pathogenic mutations. , 2000, Science.

[17]  Y Li,et al.  [Mitochondria and apoptosis]. , 2000, Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine].

[18]  C. Heldin,et al.  Smad7 mediates apoptosis induced by transforming growth factor β in prostatic carcinoma cells , 2000, Current Biology.

[19]  J. Massagué,et al.  Transcriptional control by the TGF‐β/Smad signaling system , 2000 .

[20]  J. Wrana,et al.  Smads as transcriptional co-modulators. , 2000, Current opinion in cell biology.

[21]  J. Massagué,et al.  Controlling TGF-β signaling , 2000, Genes & Development.

[22]  A. Signore,et al.  Identification and Characterization of a Ligand-independent Oligomerization Domain in the Extracellular Region of the CD95 Death Receptor* , 1999, The Journal of Biological Chemistry.

[23]  T. Nakashima,et al.  Activation of caspase‐8 in transforming growth factor‐β–induced apoptosis of human hepatoma cells , 1999, Hepatology.

[24]  K. Miyazono,et al.  Roles of bone morphogenetic protein type I receptors and Smad proteins in osteoblast and chondroblast differentiation. , 1999, Molecular biology of the cell.

[25]  S. Korsmeyer,et al.  Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis , 1999, Nature.

[26]  E. Solary,et al.  Fas Ligand-independent, FADD-mediated Activation of the Fas Death Pathway by Anticancer Drugs* , 1999, The Journal of Biological Chemistry.

[27]  D. Tang,et al.  Cycloheximide-induced T-cell Death Is Mediated by a Fas-associated Death Domain-dependent Mechanism* , 1999, The Journal of Biological Chemistry.

[28]  S. Kern,et al.  G1 cell cycle arrest and apoptosis induction by nuclear Smad4/Dpc4: phenotypes reversed by a tumorigenic mutation. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[29]  Y. Goltsev,et al.  Tumor necrosis factor receptor and Fas signaling mechanisms. , 1999, Annual review of immunology.

[30]  S H Kaufmann,et al.  Mammalian caspases: structure, activation, substrates, and functions during apoptosis. , 1999, Annual review of biochemistry.

[31]  G. Gores,et al.  Toxic bile salts induce rodent hepatocyte apoptosis via direct activation of Fas. , 1999, The Journal of clinical investigation.

[32]  R. Derynck,et al.  Transcriptional Activators of TGF-β Responses: Smads , 1998, Cell.

[33]  Y. Yatabe,et al.  Induction of apoptosis by Smad3 and down-regulation of Smad3 expression in response to TGF-β in human normal lung epithelial cells , 1998, Oncogene.

[34]  S. Cory,et al.  The Bcl-2 protein family: arbiters of cell survival. , 1998, Science.

[35]  Y. Lazebnik,et al.  Caspases: enemies within. , 1998, Science.

[36]  Junying Yuan,et al.  Cleavage of BID by Caspase 8 Mediates the Mitochondrial Damage in the Fas Pathway of Apoptosis , 1998, Cell.

[37]  A. Saltzman,et al.  Transforming Growth Factor-β-Mediated Apoptosis in the Ramos B-Lymphoma Cell Line Is Accompanied by Caspase Activation and Bcl-XLDownregulation , 1998 .

[38]  Robert Munro,et al.  Transforming growth factor-beta-mediated apoptosis in the Ramos B-lymphoma cell line is accompanied by caspase activation and Bcl-XL downregulation. , 1998, Experimental cell research.

[39]  Kohei Miyazono,et al.  TGF-β signalling from cell membrane to nucleus through SMAD proteins , 1997, Nature.

[40]  G. Salvesen,et al.  Caspases: Intracellular Signaling by Proteolysis , 1997, Cell.

[41]  S. Srinivasula,et al.  Cytochrome c and dATP-Dependent Formation of Apaf-1/Caspase-9 Complex Initiates an Apoptotic Protease Cascade , 1997, Cell.

[42]  R. Derynck,et al.  TGF- receptor signaling , 1997 .

[43]  A. Chinnaiyan,et al.  Ultraviolet Radiation-induced Apoptosis Is Mediated by Activation of CD-95 (Fas/APO-1)* , 1997, The Journal of Biological Chemistry.

[44]  C. Heldin,et al.  Identification of Smad7, a TGFβ-inducible antagonist of TGF-β signalling , 1997, Nature.

[45]  K. Miyazono,et al.  Smad6 inhibits signalling by the TGF-β superfamily , 1997, Nature.

[46]  R. H. Chen,et al.  Involvement of caspase family proteases in transforming growth factor-beta-induced apoptosis. , 1997, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[47]  J. Wrana,et al.  The MAD-Related Protein Smad7 Associates with the TGFβ Receptor and Functions as an Antagonist of TGFβ Signaling , 1997, Cell.

[48]  Y. Bang,et al.  Establishment and characterization of human gastric carcinoma cell lines , 1997, International journal of cancer.

[49]  J. Massagué,et al.  BMP signaling and vertebrate limb development. , 1997, Cold Spring Harbor symposia on quantitative biology.

[50]  김성진.  Transforming Growth Factor-βs , 1996 .

[51]  Georgy Koentges,et al.  Neural Crest Apoptosis and the Establishment of Craniofacial Pattern: An Honorable Death , 1996, Molecular and Cellular Neuroscience.

[52]  David Wallach,et al.  Involvement of MACH, a Novel MORT1/FADD-Interacting Protease, in Fas/APO-1- and TNF Receptor–Induced Cell Death , 1996, Cell.

[53]  M. Auffredou,et al.  Characterization of transforming growth factor-beta 1 induced apoptosis in normal human B cells and lymphoma B cell lines. , 1995, Oncogene.

[54]  Arul M. Chinnaiyan,et al.  FADD, a novel death domain-containing protein, interacts with the death domain of fas and initiates apoptosis , 1995, Cell.

[55]  J. Camonis,et al.  A Novel Protein That Interacts with the Death Domain of Fas/APO1 Contains a Sequence Motif Related to the Death Domain (*) , 1995, The Journal of Biological Chemistry.

[56]  Takashi Suda,et al.  Molecular cloning and expression of the fas ligand, a novel member of the tumor necrosis factor family , 1993, Cell.

[57]  N. Fausto.  Hepatocyte apoptosis: is transforming growth factor-B1 the kiss of death? , 1993, Hepatology.

[58]  W. Bursch,et al.  Induction of apoptosis in cultured hepatocytes and in regressing liver by transforming growth factor beta 1. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[59]  Atsushi Hase,et al.  The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis , 1991, Cell.

[60]  Anita B. Roberts,et al.  Peptide Growth Factors and Their Receptors I , 1990, Springer Study Edition.

[61]  M. Sporn,et al.  The Transforming Growth Factor-βs , 1991 .

[62]  P. Möller,et al.  Monoclonal antibody-mediated tumor regression by induction of apoptosis. , 1989, Science.

[63]  S. Yonehara,et al.  A cell-killing monoclonal antibody (anti-Fas) to a cell surface antigen co-downregulated with the receptor of tumor necrosis factor , 1989, The Journal of experimental medicine.