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Inducing Apoptosis in Cancer

Inducing Apoptosis in Cancer. Apoptosis is an Essential Process. Apoptosis (programmed cell death) plays an important role in normal development and homeostasis Apoptosis is activated through two principal signaling pathways: intrinsic and extrinsic 1 – 2

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Inducing Apoptosis in Cancer

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  1. Inducing Apoptosis in Cancer

  2. Apoptosis is an Essential Process • Apoptosis (programmed cell death) plays an important rolein normal development and homeostasis • Apoptosis is activated through two principal signaling pathways: intrinsic and extrinsic1–2 • Cancer is often initiated by DNA damage • Normal cells undergo apoptosis in response to stress-inducing events in the cell, such as DNA damage • Dysregulation of apoptosis is critical for cancer development and tumor cell survival3

  3. Overview of the Two Major Apoptosis Pathways Pro-apoptotic ligand Cell-extrinsicpathway Pro-apoptotic receptor Caspases BAX Mitochondria BCL2 PUMA Cell-intrinsicpathway Stress Apoptosis Adapted from Ashkenazi A. Nat Rev Cancer 2002;2:420–430.BAX, BCL2-associated protein; BCL2, B-cell chronic lymphocytic leukemia/lymphoma 2; PUMA, p53-upregulated modulator of apoptosis.

  4. Apoptosis Apoptosis is Carried out by Caspases Pro-apoptotic stimulus Initiator caspases Caspase cascade Effector caspases Adapted from Thornberry NA, Lazebnik Y. Science 1998;281:1312–1316.Caspase, cysteine aspartase.

  5. p53 p53 BAX, BAK Apoptosis The Intrinsic Apoptosis Pathway ChemotherapyRadiotherapy DNA damage Cell-intrinsicpathway PUMA, NOXA BCL2, BCLXL, MCL1 Mitochondria Cytochrome c SMAC/DIABLO APAF1 Caspase 9 IAP Caspase 3, 6, 7 p53 DNA damage Adapted from Ashkenazi A. Nat Rev Cancer 2002;2:420–430.APAF1, apoptotic protease activating factor-1; BAK, BCL2 homologous antagonist/killer; BAX, BCL2-associated protein; BCL2, B-cell chronic lymphocytic leukemia/lymphoma 2; BCLXL, BCL2-like 1; IAP, inhibitor of apoptosis protein;MCL1, myeloid cell leukemia sequence 1 (BCL2-related); PUMA, p53-upregulated modulator of apoptosis; SMAC/DIABLO: second mitochondria-derived activator of caspase/direct IAP binding protein with low pI.

  6. The Intrinsic Apoptosis Pathway • The intrinsic pathway is triggered by the p53 tumor-suppressor in response to DNA damage and other types of severe cell stress • Conventional anticancer therapies, such as chemotherapy and radiotherapy, activate this pathway via p53 • p53 activates the intrinsic pathway through transcriptional upregulation of pro-apoptotic members of the BCL2 family of proteins such as PUMA and BAX • BAX causes the release of cytochrome c from the mitochondria, which together with the adaptor APAF1, activate the initiator caspase 9 • Caspase 9 activates the effector caspases 3, 6, and 7, which are responsible for destroying critical components of the cell, and inducing apoptosis • p53 is inactivated by mutations in more than half of human cancers

  7. The Extrinsic Apoptosis Pathway Pro-apoptotic ligand Cell-extrinsicpathway DR5 DR4 FADD FLIP Procaspase 8, 10 Caspase 8, 10 Caspase 3, 6, 7 Apoptosis Adapted from Ashkenazi A. Nat Rev Cancer 2002;2:420–430.FADD, Fas-associated death domain; FLIP, FLICE (FADD-like interleukin 1β-converting enzyme) inhibitory protein.

  8. The Extrinsic Apoptosis Pathway • The extrinsic pathway triggers apoptosis in response to the activation of pro-apoptotic receptors, such as DR4 and DR5, by specific pro-apoptotic ligands, such as Apo2L/TRAIL • This pathway stimulates apoptosis independently of p53 • Ligand-induced activation of DR4 and DR5 leads to the rapid assembly of the death-inducing signaling complex (DISC) and the recruitment of initiator caspases 8 and 10 through the adaptor Fas-associated death domain (FADD) • Caspases 8 and 10 activate effector caspases 3, 6, and 7, leading to apoptosis

  9. FLIP p53 p53 The Two Major Apoptosis Pathways Pro-apoptotic ligand Cell-extrinsicpathway ChemotherapyRadiotherapy DR5 DR4 DNA damage Cell-intrinsicpathway p53 FADD PUMA, NOXA BCL2, BCLXL, MCL1 BID BAX, BAK Procaspase 8, 10 Mitochondria Caspase 8, 10 Cytochrome c SMAC/DIABLO APAF1 Caspase 9 IAP Caspase 3, 6, 7 Apoptosis DNA damage Adapted from Ashkenazi A. Nat Rev Can 2002;2:420–430.APAF1, apoptotic protease activating factor-1; BAK, BCL2 homologous antagonist/killer; BAX, BCL2-associated protein; BCL2, B-cell chronic lymphocytic leukemia/lymphoma2; BCLXL, BCL2-like 1; BID, BH3-interacting domain death agonist; DR, death receptor; FADD, Fas-associated death domain; FLIP, FLICE (FADD-like interleukin 1β-converting enzyme) inhibitory protein; IAP, inhibitor of apoptosis protein;MCL1, myeloid cell leukemia sequence 1 (BCL2-related); PUMA, p53-upregulated modulator of apoptosis; SMAC/DIABLO: second mitochondria-derived activator of caspase/direct IAP binding protein with low pI.

  10. Apoptosis via Pro-apoptotic Receptors (DR4 and DR5) Endogenous Apo2L/TRAIL DR4 DR5 Apo2L/TRAIL, apoptosis-inducing ligand 2/tumor necrosis factor-related apoptosis-inducing ligand; DR, death receptor.

  11. Endogenous Apo2L/TRAIL ActivatesPro-apoptotic Receptors (DR4 and DR5) DR4 DR5 DR, death receptor.

  12. FADD Pro-apoptotic Receptors (DR4 and/or DR5)Recruit FADD DR4 DR5 DR, death receptor; FADD, Fas-associated death domain.

  13. FADD Recruits Initiator Caspase 8 and/or 10 to the DISC DR4 DR5 DISC Procaspase 8, 10 Procaspase 8, 10 DR, death receptor; DISC, death-inducing signaling complex.

  14. Activated Caspase 8 and 10 are Released Into the Cytoplasm DR4 DR5 Caspase 8,10 Caspase 8,10 DR, death receptor.

  15. Caspase 3, 6, and 7 are Activated DR4 DR5 Caspase 8, 10 Caspase 8, 10 Caspase 3, 6, 7 Caspase 3, 6, 7 DR, death receptor.

  16. FLIP p53 p53 Activated Caspase 3, 6, and 7 ExecuteApoptosis in Tumor Cells Pro-apoptotic ligand Cell-extrinsicpathway ChemotherapyRadiotherapy DR5 DR4 DNA damage Cell-intrinsicpathway p53 FADD PUMA, NOXA BCL2, BCLXL, MCL1 BID BAX, BAK Procaspase 8, 10 Mitochondria Caspase 8, 10 Cytochrome c SMAC/DIABLO APAF1 Caspase 9 IAP Caspase 3, 6, 7 Apoptosis DNA damage Adapted from Ashkenazi A. Nat Rev Cancer 2002;2:420–430.APAF1, apoptotic protease activating factor-1; BAK, BCL2 homologous antagonist/killer; BAX, BCL2-associated protein; BCL2, B-cell chronic lumphocytic leukemia/lymphoma 2; BCLXL, BCL2-like 1; BID, BH3-interacting domain death agonist; DR, death receptor; FADD, Fas-associated death domain; FLIP, FLICE (FADD-like interleukin 1β-converting enzyme) inhibitory protein; IAP, inhibitor of apoptosis protein;MCL1, myeloid cell leukemia sequence 1 (BCL2-related); PUMA, p53-upregulated modulator of apoptosis; SMAC/DIABLO: second mitochondria-derived activator of caspase/direct IAP binding protein with low pI.

  17. References • Ashkenazi A. Targeting death and decoy receptors of the tumor-necrosis factor superfamily. Nat Rev Cancer 2002;2:420–430. • Ghobrial IM, Witzig TE, Adjei AA. Targeting apoptosis pathways in cancer therapy. CA Cancer J Clin 2005;55:178–194. • Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57–70. • Thornberry NA, Lazebnik Y. Caspases: Enemies within. Science 1998;281:1312–1316. • Ashkenazi A, Pai RC, Fong S, et al. Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest 1999;104:155–162. • Lowe SW, Bodis S, McClatchey A, et al. p53 status and the efficacy of cancer therapy in vivo. Science 1994;266:807–810. • Lee JM, Bernstein A. Apoptosis, cancer, and the p53 tumor suppressor gene. Cancer Metastasis Rev 1995;14:149–161. • Igney FH, Krammer PH. Death and anti-death: tumor resistance to apoptosis. Nat Rev Cancer 2002;2:277–288.

  18. References (cont’d) • Pan G, O’Rourke K, Chinnaiyan AM, et al. The receptor for the cytotoxic ligand TRAIL. Science 1997;276:111–113. • Sheridan JP, Marsters SA, Pitti RM, et al. Control of TRAIL-induced apoptosis by the family of signaling and decoy receptors. Science 1997;277:818–821. • Pitti RM, Marsters SA, Ruppert S, et al. Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem 1996;271:12687–12690. • Wiley SR, Schooley K, Smolak PJ, et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 1995;3:673–682. • Gazitt Y. TRAIL is a potent inhibitor of apoptosis in myeloma cells derived from multiple myeloma patients and is not cytotoxic to hematopoietic stem cells. Leukemia 1999;13:1817–1824. • Pollack IF, Erff M, Ashkenazi A. Direct stimulation of apoptotic signaling by soluble Apo2L/tumor necrosis factor-related apoptosis-inducing ligand leads to selective killing of glioma cells. Clin Cancer Res 2001;7:1362–1369.

  19. References (cont’d) • Qin J-Z, Chaturvedi V, Bonish B, Nickoloff BJ. Avoiding premature apoptosis of normal epidermal cells. Nat Med 2001;7:385–386. • Kischkel FC, Lawrence DA, Chuntharapai A, et al. Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. Immunity 2000;12:611–620. • Chinnaiyan AM, O’Rourke K, Tewari M, Dixit VM. FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell 1995;81:505–512. • Kischkel FC, Lawrence DA, Tinel A, et al. Death receptor recruitment of endogenous caspase-10 and apoptosis initiation in the absence of caspase-8. J Biol Chem 2001;276:46639–46646. • Griffith TS, Lynch DH. TRAIL: a molecule with multiple receptors and control mechanisms. Curr Opin Immunol 1998;10:559–563. • Pukac L, Kanakaraj P, Humphreys R, et al. HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumor types in vitro and in vivo. Br J Cancer 2005;92:1430–1441.

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