Top

Published in:

01-08-2011 | Focussed Research Review

Targeting the extrinsic apoptosis signaling pathway for cancer therapy

Author: Thomas J. Sayers

Published in: Cancer Immunology, Immunotherapy | Issue 8/2011

Abstract

The extrinsic apoptosis pathway is triggered by the binding of death ligands of the tumor necrosis factor (TNF) family to their appropriate death receptors (DRs) on the cell surface. One TNF family member, TNF-related apoptosis-inducing ligand (TRAIL or Apo2L), seems to preferentially cause apoptosis of transformed cells and can be systemically administered in the absence of severe toxicity. Therefore, there has been enthusiasm for the use of TRAIL or agonist antibodies to the TRAIL DR4 and DR5 in cancer therapy. Nonetheless, many cancer cells are very resistant to TRAIL apoptosis in vitro. Therefore, there is much interest in identifying compounds that can be combined with TRAIL to amplify its apoptotic effects. In this review, I will provide a brief overview of apoptosis signaling by TRAIL and discuss apoptosis-sensitizing agents, focusing mainly on the proteasome inhibitor bortezomib (VELCADE) and some novel sensitizers that we have recently identified. Alternative ways to administer TRAIL or DR agonist antibodies as therapeutic agents will also be described. Finally, I will discuss some of the gaps in our understanding of TRAIL apoptosis signaling and suggest some research directions that may provide additional information for optimizing the targeting of the extrinsic apoptosis pathway for future cancer therapy.

Coultas L, Strasser A (2003) The role of the Bcl-2 protein family in cancer. Semin Cancer Biol 13:115–123PubMedCrossRef

Green DR, Marante-Mendes GP (1998) The point of no return: mitochondria, caspases, and the commitment to cell death. Results Probl Cell Differ 24:45–61PubMed

Salvesen GS, Duckett CS (2002) IAP proteins: blocking the road to death’s door. Nat Rev Mol Cell Biol 3:401–410PubMedCrossRef

Gonzalvez F, Ashkenazi A (2010) New insights into apoptosis signaling by Apo2L/TRAIL. Oncogene 29:4752–4765PubMedCrossRef

Oldenhuis CNAM, Stegehuis JH, Walenkamp AME, de Jong S, de Vries EGE (2008) Targeting TRAIL death receptors. Curr Opin Pharmacol 8:433–439PubMedCrossRef

Ashkenazi A, Herbst RS (2008) To kill a tumor cell: the potential of proapoptotic receptor agonists. J Clin Invest 118:1979–1990PubMedCrossRef

Wiley SR, Schooley K, Smolak PJ, Din WS, Huang C-P, Nicholl JK, Sutherland GR, Smith CA, Goodwin RG (1995) Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 3:673–682PubMedCrossRef

Pitti RM, Marsters SA, Ruppert S, Donahue CJ, Moore A, Ashkenazi A (1996) Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem 271:12687–12690PubMedCrossRef

Peter ME, Krammer PH (2003) The CD95(APO-1/Fas) DISC and beyond. Cell Death Differ 10:26–35PubMedCrossRef

10.

Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V, Bodmer JL, Schroter M, Burns K, Mattmann C, Rimoldi D, French LE, Tschopp J (1997) Inhibition of death receptor signals by cellular FLIP. Nature 388:190–195PubMedCrossRef

11.

Wagner KW, Punnoose EA, Januario T, Lawrence DA, Pitti RM, Lancaster K, Lee D, von Goetz M, Yee SF, Totpal K, Huw L, Katta V, Cavet G, Hymowitz SG, Amler L, Ashkenazi A (2007) Death-receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L/TRAIL. Nat Med 13:1070–1077PubMedCrossRef

12.

Jin Z, Li Y, Pitti R, Lawrence D, Pham VC, Lill JR, Ashkenazi A (2009) Cullin3-based polyubiquitination and p62-dependent aggregation of caspase-8 mediate extrinsic apoptosis signaling. Cell 137:721–735PubMedCrossRef

13.

Scaffidi C, Schmitz I, Zha J, Korsmeyer SJ, Krammer PH, Peter ME (1999) Differential modulation of apoptosis sensitivity in CD95 type I and type II cells. J Biol Chem 274:22532–22538PubMedCrossRef

14.

Ozoren N, el Deiry WS (2002) Defining characteristics of Types I and II apoptotic cells in response to TRAIL. Neoplasia 4:551–557PubMedCrossRef

15.

Li H, Zhu H, Xu CJ, Yuan J (1998) Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94:491–501PubMedCrossRef

16.

Luo X, Budihardjo I, Zou H, Slaughter C, Wang X (1998) Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94:481–490PubMedCrossRef

17.

Mahalingam D, Szegezdi E, Keane M, de Jong S, Samali A (2009) TRAIL receptor signalling and modulation: are we on the right TRAIL? Cancer Treat Rev 35:280–288PubMedCrossRef

18.

Sayers TJ, Murphy WJ (2006) Combining proteasome inhibition with TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) for cancer therapy. Cancer Immunol Immunother 55:76–84PubMedCrossRef

19.

Ganten TM, Koschny R, Haas TL, Sykora J, Li-Weber M, Herzer K, Walczak H (2005) Proteasome inhibition sensitizes hepatocellular carcinoma cells, but not human hepatocytes, to TRAIL. Hepatology 42:588–597PubMedCrossRef

20.

Koschny R, Ganten TM, Sykora J, Haas TL, Sprick MR, Kolb A, Stremmel W, Walczak H (2007) TRAIL/bortezomib cotreatment is potentially hepatotoxic but induces cancer-specific apoptosis within a therapeutic window. Hepatology 45:649–658PubMedCrossRef

21.

Shanker A, Brooks AD, Tristan CA, Wine JW, Elliott PJ, Yagita H, Takeda K, Smyth MJ, Murphy WJ, Sayers TJ (2008) Treating metastatic solid tumors with bortezomib and a tumor necrosis factor-related apoptosis-inducing ligand receptor agonist antibody. J Natl Cancer Inst 100:649–662PubMedCrossRef

22.

Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD, Maas J, Pien CS, Prakash S, Elliott PJ (1999) Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 59:2615–2622PubMed

23.

Liu X, Yue P, Chen S, Hu L, Lonial S, Khuri FR, Sun SY (2007) The proteasome inhibitor PS-341 (bortezomib) up-regulates DR5 expression leading to induction of apoptosis and enhancement of TRAIL-induced apoptosis despite up-regulation of c-FLIP and survivin expression in human NSCLC cells. Cancer Res 67:4981–4988PubMedCrossRef

24.

Kandasamy K, Kraft AS (2008) Proteasome inhibitor PS-341 (VELCADE) induces stabilization of the TRAIL receptor DR5 mRNA through the 3′-untranslated region. Mol Cancer Ther 7:1091–1100PubMedCrossRef

25.

Koschny R, Holland H, Sykora J, Haas TL, Sprick MR, Ganten TM, Krupp W, Bauer M, Ahnert P, Meixensberger J, Walczak H (2007) Bortezomib sensitizes primary human astrocytoma cells of WHO grades I to IV for tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Clin Cancer Res 13:3403–3412PubMedCrossRef

26.

Luster TA, Carrell JA, McCormick K, Sun D, Humphreys R (2009) Mapatumumab and lexatumumab induce apoptosis in TRAIL-R1 and TRAIL-R2 antibody-resistant NSCLC cell lines when treated in combination with bortezomib. Mol Cancer Ther 8:292–302PubMedCrossRef

27.

Brooks AD, Jacobsen KM, Li W, Shanker A, Sayers TJ (2010) Bortezomib sensitizes human renal cell carcinomas to TRAIL apoptosis through increased activation of caspase-8 in the death-inducing signaling complex. Mol Cancer Res 8:729–738PubMedCrossRef

28.

Sayers TJ, Brooks AD, Koh CY, Ma W, Seki N, Raziuddin A, Blazar BR, Zhang X, Elliott PJ, Murphy WJ (2003) The proteasome inhibitor PS-341 sensitizes neoplastic cells to TRAIL-mediated apoptosis by reducing levels of c-FLIP. Blood 102:303–310PubMedCrossRef

29.

Kabore AF, Sun J, Hu X, McCrea K, Johnston JB, Gibson SB (2006) The TRAIL apoptotic pathway mediates proteasome inhibitor induced apoptosis in primary chronic lymphocytic leukemia cells. Apoptosis 11:1175–1193PubMedCrossRef

30.

Nikrad M, Johnson T, Puthalalath H, Coultas L, Adams J, Kraft AS (2005) The proteasome inhibitor bortezomib sensitizes cells to killing by death receptor ligand TRAIL via BH3-only proteins Bik and Bim. Mol Cancer Ther 4:443–449PubMed

31.

Seki N, Toh U, Sayers TJ, Fujii T, Miyagi M, Akagi Y, Kusukawa J, Kage M, Shirouzu K, Yamana H (2010) Bortezomib sensitizes human esophageal squamous cell carcinoma cells to TRAIL-mediated apoptosis via activation of both extrinsic and intrinsic apoptosis pathways. Mol Cancer Ther 9:1842–1851PubMedCrossRef

32.

Booth NL, Sayers TJ, Brooks AD, Thomas CL, Jacobsen K, Goncharova EI, McMahon JB, Henrich CJ (2009) A cell-based high-throughput screen to identify synergistic TRAIL sensitizers. Cancer Immunol Immunother 58:1229–1244PubMedCrossRef

33.

Lee T-J, Um HJ, Min DS, Park J-W, Choi KS, Kwon TK (2009) Withaferin A sensitizes TRAIL-induced apoptosis through reactive oxygen species-mediated up-regulation of death receptor 5 and down-regulation of c-FLIP. Free Radic Biol Med 46:1639–1649PubMedCrossRef

34.

Lee AH, Iwakoshi NN, Anderson KC, Glimcher LH (2003) Proteasome inhibitors disrupt the unfolded protein response in myeloma cells. Proc Natl Acad Sci USA 100:9946–9951PubMedCrossRef

35.

Nawrocki ST, Carew JS, Dunner K Jr, Boise LH, Chiao PJ, Huang P, Abbruzzese JL, McConkey DJ (2005) Bortezomib inhibits PKR-like endoplasmic reticulum (ER) kinase and induces apoptosis via ER stress in human pancreatic cancer cells. Cancer Res 65:11510–11519PubMedCrossRef

36.

Huang S, Sinicrope FA (2008) BH3 mimetic ABT-737 potentiates TRAIL-mediated apoptotic signaling by unsequestering Bim and Bak in human pancreatic cancer cells. Cancer Res 68:2944–2951PubMedCrossRef

37.

Nguyen M, Marcellus RC, Roulston A, Watson M, Serfass L, Murthy M Sr, Goulet D, Viallet J, Belec L, Billot X, Acoca S, Purisima E, Wiegmans A, Cluse L, Johnstone RW, Beauparlant P, Shore GC (2007) Small molecule obatoclax (GX15–070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc Natl Acad Sci USA 104:19512–19517PubMedCrossRef

38.

Xu Z, Friess H, Solioz M, Aebi S, Korc M, Kleeff J, Buchler MW (2001) Bcl-x(L) antisense oligonucleotides induce apoptosis and increase sensitivity of pancreatic cancer cells to gemcitabine. Int J Cancer 94:268–274PubMedCrossRef

39.

LaCasse EC, Cherton-Horvat GG, Hewitt KE, Jerome LJ, Morris SJ, Kandimalla ER, Yu D, Wang H, Wang W, Zhang R, Agrawal S, Gillard JW, Durkin JP (2006) Preclinical characterization of AEG35156/GEM 640, a second-generation antisense oligonucleotide targeting X-linked inhibitor of apoptosis. Clin Cancer Res 12:5231–5241PubMedCrossRef

40.

Fulda S, Wick W, Weller M, Debatin KM (2002) Smac agonists sensitize for Apo2L/T-or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. Nat Med 8:808–815PubMed

41.

Vogler M, Walczak H, Stadel D, Haas TL, Genze F, Jovanovic M, Bhanot U, Hasel C, Moller P, Gschwend JE, Simmet T, Debatin KM, Fulda S (2009) Small molecule XIAP inhibitors enhance TRAIL-induced apoptosis and antitumor activity in preclinical models of pancreatic carcinoma. Cancer Res 69:2425–2434PubMedCrossRef

42.

Wang Z, Cuddy M, Samuel T, Welsh K, Schimmer A, Hanaii F, Houghten R, Pinilla C, Reed JC (2004) Cellular, biochemical, and genetic analysis of mechanism of small molecule IAP inhibitors. J Biol Chem 279:48168–48176PubMedCrossRef

43.

Jost PJ, Grabow S, Gray D, McKenzie MD, Nachbur U, Huang DC, Bouillet P, Thomas HE, Borner C, Silke J, Strasser A, Kaufmann T (2009) XIAP discriminates between type I and type II FAS-induced apoptosis. Nature 460:1035–1039PubMedCrossRef

44.

Griffith TS, Anderson RD, Davidson BL, Williams RD, Ratliff TL (2000) Adenoviral-mediated transfer of the TNF-related apoptosis-inducing ligand/Apo-2 ligand gene induces tumor cell apoptosis. J Immunol 165:2886–2894PubMed

45.

Holoch PA, Griffith TS (2009) TNF-related apoptosis-inducing ligand (TRAIL): a new path to anti-cancer therapies. Eur J Pharmacol 625:63–72PubMedCrossRef

46.

Vanoosten RL, Griffith TS (2007) Activation of tumor-specific CD8+T Cells after intratumoral Ad5-TRAIL/CpG oligodeoxynucleotide combination therapy. Cancer Res 67:11980–11990PubMedCrossRef

47.

Uno T, Takeda K, Kojima Y, Yoshizawa H, Akiba H, Mittler RS, Gejyo F, Okumura K, Yagita H, Smyth MJ (2006) Eradication of established tumors in mice by a combination antibody-based therapy. Nat Med 12:693–698PubMedCrossRef

48.

Shanker A, Brooks AD, Jacobsen KM, Wine JW, Wiltrout RH, Yagita H, Sayers TJ (2009) Antigen presented by tumors in vivo determines the nature of CD8+T-cell cytotoxicity. Cancer Res 69:6615–6623PubMedCrossRef

49.

Chen L, Park SM, Tumanov AV, Hau A, Sawada K, Feig C, Turner JR, Fu YX, Romero IL, Lengyel E, Peter ME (2010) CD95 promotes tumour growth. Nature 465:492–496PubMedCrossRef

50.

Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A, Posati S, Rogaia D, Frassoni F, Aversa F, Martelli MF, Velardi A (2002) Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295:2097–2100PubMedCrossRef

51.

Hallett WH, Ames E, Motarjemi M, Barao I, Shanker A, Tamang DL, Sayers TJ, Hudig D, Murphy WJ (2008) Sensitization of tumor cells to NK cell-mediated killing by proteasome inhibition. J Immunol 180:163–170PubMed

52.

Lundqvist A, Yokoyama H, Smith A, Berg M, Childs R (2009) Bortezomib treatment and regulatory T-cell depletion enhance the antitumor effects of adoptively infused NK cells. Blood 113:6120–6127PubMedCrossRef

53.

Lundqvist A, Abrams SI, Schrump DS, Alvarez G, Suffredini D, Berg M, Childs R (2006) Bortezomib and depsipeptide sensitize tumors to tumor necrosis factor-related apoptosis-inducing ligand: a novel method to potentiate natural killer cell tumor cytotoxicity. Cancer Res 66:7317–7325PubMedCrossRef

54.

Sudbery I, Enright AJ, Fraser AG, Dunham I (2010) Systematic analysis of off-target effects in an RNAi screen reveals microRNAs affecting sensitivity to TRAIL-induced apoptosis. BMC Genomics 11:175PubMedCrossRef

55.

Aza-Blanc P, Cooper CL, Wagner K, Batalov S, Deveraux QL, Cooke MP (2003) Identification of modulators of TRAIL-induced apoptosis via RNAi-based phenotypic screening. Mol Cell 12:627–637PubMedCrossRef

56.

Ovcharenko D, Kelnar K, Johnson C, Leng N, Brown D (2007) Genome-scale microRNA and small interfering RNA screens identify small RNA modulators of TRAIL-induced apoptosis pathway. Cancer Res 67:10782–10788PubMedCrossRef

57.

Yang TM, Barbone D, Fennell DA, Broaddus VC (2009) Bcl-2 family proteins contribute to apoptotic resistance in lung cancer multicellular spheroids. Am J Respir Cell Mol Biol 41:14–23PubMedCrossRef

58.

Finnberg N, Klein-Szanto AJ, El-Deiry WS (2008) TRAIL-R deficiency in mice promotes susceptibility to chronic inflammation and tumorigenesis. J Clin Invest 118:111–123PubMedCrossRef

59.

Grosse-Wilde A, Voloshanenko O, Bailey SL, Longton GM, Schaefer U, Csernok AI, Schutz G, Greiner EF, Kemp CJ, Walczak H (2008) TRAIL-R deficiency in mice enhances lymph node metastasis without affecting primary tumor development. J Clin Invest 118:100–110PubMedCrossRef

Title: Targeting the extrinsic apoptosis signaling pathway for cancer therapy
Author: Thomas J. Sayers
Publication date: 01-08-2011
Publisher: Springer-Verlag
Published in: Cancer Immunology, Immunotherapy / Issue 8/2011
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-011-1008-4

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 8/2011

Camouflage and sabotage: tumor escape from the immune system

Intraperitoneal administration of poly(I:C) with polyethylenimine leads to significant antitumor immunity against murine ovarian tumors

DNA fusion vaccines enter the clinic

Phase I/II study of adoptive transfer of γδ T cells in combination with zoledronic acid and IL-2 to patients with advanced renal cell carcinoma

Tenth International Conference on Progress in Vaccination Against Cancer (PIVAC 10), Cambridge, UK, 27th–30th September 2010: New hopes and strategies for cancer vaccines

Cooperativity of adaptive and innate immunity: implications for cancer therapy

Keynote webinar | Spotlight on antibody–drug conjugates in cancer