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Cancer Immunology, Immunotherapy
Published in: Cancer Immunology, Immunotherapy 3/2004

01-03-2004 | Review

Apoptosis pathways in cancer and cancer therapy

Author: Klaus-Michael Debatin

Published in: Cancer Immunology, Immunotherapy | Issue 3/2004

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Abstract

Activation of apoptosis pathways is a key mechanism by which cytotoxic drugs kill tumor cells. Also immunotherapy of tumors requires an apoptosis sensitive phenotype of target cells. Defects in apoptosis signalling contribute to resistance of tumors. Activation of apoptosis signalling following treatment with cytotoxic drugs has been shown to lead to activation of the mitochondrial (intrinsic) pathway of apoptosis. In addition, signalling through the death receptor (extrinsic) pathways, contributes to sensitivity of tumor cells towards cytotoxic treatment. Both pathways converge finally at the level of activation of caspases, the effector molecules in most forms of cell death. In addition to classical apoptosis, non-apoptotic modes of cell death have recently been identified. Mechanisms to overcome apoptosis resistance include direct targeting of antiapoptotic molecules expressed in tumors as well as re-sensitization of previously resistant tumor cells by re-expression of caspases and counteracting apoptotis inhibitory molecules such as Bcl-2 and molecules of the IAP family of endogenous caspase inhibitors. Molecular insights into regulation of apoptosis and defects in apoptosis signalling in tumor cells will provide novel approaches to define sensitivity or resistance of tumor cells towards antitumor therapy and provide new targets for rational therapeutic interventions for future therapeutic strategies.
Literature
1.
Debatin KM (1999) The role of the CD95 system in chemotherapy. In: Broxterman HJA (ed) Drug resistance updates. Churchill Livingstone, Edinburgh, pp 85–90
2.
Herr I, Debatin KM (2001) Cellular stress response and apoptosis in cancer therapy. Blood 98:2603–2614CrossRefPubMed
3.
Debatin, KM (1997) Anticancer drugs, programmed cell death and the immune system: defining new roles in an old play. J Natl Cancer Inst 89:750–753CrossRefPubMed
4.
Kaufmann SH, Earnshaw WC (2000) Induction of apoptosis by cancer chemotherapy. Exp Cell Res 256:42–49CrossRefPubMed
5.
Solary E, Droin N, Bettaieb A, Corcos L, Dimanche-Boitrel MT, Garrido C (2000) Positive and negative regulation of apoptotic pathways by cytotoxic agents in hematological malignancies. Leukemia 14:1833–1849PubMed
6.
7.
8.
9.
10.
Leppa S, Bohmann D (1999) Diverse functions of JNK signaling and c-Jun in stress response and apoptosis. Oncogene 18:6158–6162PubMed
11.
Davis RJ (2000) Signal transduction by the JNK group of MAP kinases. Cell 103:239–252PubMed
12.
Mayo MW, Baldwin AS (2000) The transcription factor NF-kB: control of oncogenesis and cancer therapy resistance. Biochim Biophys Acta 1470:M55–M62CrossRefPubMed
13.
14.
Los M, Wesselborg S, Schulze-Osthoff K (1999) The role of caspases in development, immunity, and apoptotic signal transduction: lessons from knockout mice. Immunity 10:629–639PubMed
15.
Degen WGJ, Pruijn GJM, Raats JMH, van Venrooij WJ (2000) Caspase-dependent cleavage of nucleic acids. Cell Death Differ 7:616–627CrossRefPubMed
16.
Slee EA, Adrain C, Martin SJ (1999) Serial killers: ordering caspase activation events in apoptosis. Cell Death Differ 6:1067–1074PubMed
17.
Utz PJ, Anderson P (2000) Life and death decisions: regulation of apoptosis by proteolysis of signaling molecules. Cell Death Differ 7:589–602CrossRefPubMed
18.
Earnshaw WC, Martins LM, Kaufmann SH (1999) Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu Rev Biochem 68:383–424PubMed
19.
Kaufmann SH (1989) Induction of endonucleolytic DNA cleavage in human acute myelogenous leukemia cells by etoposide, camptothecin, and other cytotoxic anticancer drugs: a cautionary note. Cancer Res 49:5870–5878PubMed
20.
Los M, Herr I, Friesen C, Fulda S, Schulze-Osthoff K, Debatin KM (1997) Cross-resistance of CD95- and drug-induced apoptosis as a consequence of deficient activation of caspases (ICE/Ced-3 proteases). Blood 90:3118–3129PubMed
21.
Goyal L (2001) Cell death inhibition: keeping caspases in check. Cell 104:805–808PubMed
22.
Reed JC (1999) Dysregulation of apoptosis in cancer. J Clin Oncol 17:2941–2953PubMed
23.
Finkel E (1999) Does cancer therapy trigger cell suicide? Science 286:2256–2258PubMed
24.
Sperandio S, de Belle I, Bredesen DE (2001) An alternative, nonapoptotic form of programmed cell death. Proc Natl Acad Sci U S A 7:14376–14381
25.
Wyllie AH, Golstein P (2000) More than one way to go. Proc Natl Acad Sci U S A 93:11–13
26.
Borner C, Monney L (1999) Apoptosis without caspases: an inefficient molecular guillotine? Cell Death Differ 6:497–507CrossRefPubMed
27.
28.
Leist M, Jaattela M (2001) Four deaths and a funeral: from caspases to alternative mechanisms. Nat Rev Mol Cell Biol 2:589–598PubMed
29.
30.
Daugas E, Nochy D, Ravagnan L, Loeffler M, Susin SA, Zamzami N, Kroemer G (2000) Apoptosis-inducing factor (AIF): a ubiquitous mitochondrial oxidoreductase involved in apoptosis. FEBS Lett 476:118–123CrossRefPubMed
31.
Schulze-Osthoff K, Ferrari D, Los M, Wesselborg S, Peter ME (1998) Apoptosis signaling by death receptors. Eur J Biochem 4:439–459CrossRef
32.
33.
Walczak H, Krammer PH (2000) The CD95 (APO-1/Fas) and the TRAIL (APO-2L) apoptosis systems. Exp Cell Res 256:58–66PubMed
34.
Costantini P, Jacotot E, Decaudin D, Kroemer G (2000) Mitochondrion as a novel target of anticancer chemotherapy. J Natl Cancer Inst 92:1042–1053CrossRefPubMed
35.
Kroemer G, Reed JC (2000) Mitochondrial control of cell death. Nat Med 6:513–519PubMed
36.
37.
Suzuki Y, Imai Y, Nakayama H, Takahashi K, Takio K, Takahashi R (2001) A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Mol Cell 8:613–621PubMed
38.
Du C, Fang M, Li Y, Li L, Wang X (2000) Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 102:33–42PubMed
39.
Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ, Vaux DL (2000) Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 102:43–53PubMed
40.
Bratton SB, MacFarlane M, Cain K, Cohen GM (2000) Protein complexes activate distinct caspase cascades in death receptor and stress-induced apoptosis. Exp Cell Res 256:27–33CrossRefPubMed
41.
Adrain C, Martin SJ (2001) The mitochondrial apoptosome: a killer unleashed by the cytochrome seas. Trends Biochem Sci 26:390–397PubMed
42.
Li LY, Luo X, Wang X (2001) Endonuclease G is an apoptotic DNase when released from mitochondria. Nature 412:95–99PubMed
43.
Schimmer AD, Hedley DW, Penn LZ, Minden MD (2001) Receptor- and mitochondrial-mediated apoptosis in acute leukemia: a translational view. Blood 98:3541–3553CrossRefPubMed
44.
45.
Friesen C, Herr I, Krammer PH, Debatin KM (1996) Involvement of the CD95 (APO-1/FAS) receptor/ligand system in drug-induced apoptosis in leukemia cells. Nat Med 2:574–577PubMed
46.
47.
Fulda S, Sieverts H, Friesen C, Herr I, Debatin KM (1997) The CD95 (APO-1/Fas) system mediates drug-induced apoptosis in neuroblastoma cells. Cancer Res 7:3823–3829
48.
Fulda S, Los M, Friesen C, Debatin KM (1998) Chemosensitivity of solid tumor cells is associated with activation of the CD95 system. Int J Cancer 76:105–114CrossRefPubMed
49.
Fulda S, Scaffidi C, Pietsch T, Krammer PH, Peter ME, Debatin KM (1998) Activation of the CD95 (APO-1/Fas) pathway in drug- and γ-irradiation-induced apoptosis of brain tumor cells. Cell Death Differ 5:884–893CrossRefPubMed
50.
Fulda S, Susin SA, Kroemer G, Debatin KM (1998) Molecular ordering of apoptosis induced by anticancer drugs in neuroblastoma cells. Cancer Res 58:4453–4460PubMed
51.
Fulda S, Strauss G, Meyer E, Debatin KM (2000) Functional CD95 ligand and CD95 DISC in activation-induced cell death and doxorubicin-induced apoptosis in leukemic T cells. Blood 95:301–308PubMed
52.
Fulda S, Meyer E, Susin SA, Kroemer G, Debatin KM (2001) Cell type specific activation of death receptor and mitochondrial pathways in drug-induced apoptosis. Oncogene 20:1063–1075PubMed
53.
Herr I, Wilhelm D, Bohler T, Angel P, Debatin KM (1997) Activation of CD95 (APO-1/Fas) signaling by ceramide mediates cancer therapy-induced apoptosis. EMBO J 16:6200–6208PubMed
54.
Houghton JA, Harwood FG, Tillman DM (1997) Thymineless death in colon carcinoma cells is mediated via fas signaling. Proc Natl Acad Sci U S A 94:8144–8149CrossRefPubMed
55.
Muller M, Wilder S, Bannasch D, Israeli D, Lehlbach K, Li-Weber M, Friedman SL, Galle PR, Stremmel W, Oren M, Krammer PH (1998) p53 activates the CD95 (APO-1/Fas) gene in response to DNA damage by anticancer drugs. J Exp Med 188:2033–2045PubMed
56.
Muller M, Strand S, Hug H, Heinemann EM, Walczak H, Hofmann WJ, Stremmel W, Krammer PH, Galle PR (1997) Drug-induced apoptosis in hepatoma cells is mediated by the CD95 (APO-1/Fas) receptor/ligand system and involves activation of wild-type p53. J Clin Invest 99:403–413PubMed
57.
Kasibhatla S, Brunner T, Genestier L, Echeverri F, Mahboubi A, Green DR (1998) DNA damaging agents induce expression of Fas ligand and subsequent apoptosis in T lymphocytes via the activation of NF-kappa B and AP-1. Mol Cell 1:543–551PubMed
58.
Eichhorst ST, Muller M, Li-Weber M, Schulze-Bergkamen H, Angel P, Krammer PH (2000) A novel AP-1 element in the CD95 ligand promoter is required for induction of apoptosis in hepatocellular carcinoma cells upon treatment with anticancer drugs. Mol Cell Biol 20:7826–7837CrossRefPubMed
59.
Eichhorst ST, Muerkoster S, Weigand MA, Krammer PH (2001) The chemotherapeutic drug 5-fluorouracil induces apoptosis in mouse thymocytes in vivo via activation of the CD95 (APO-1/Fas) system. Cancer Res 61:243–248PubMed
60.
Beltinger C, Fulda S, Kammertoens T, Meyer E, Uckert W, Debatin KM (1999) Herpes simplex virus thymidine kinase/ganciclovir-induced apoptosis involves ligand-independent death receptor aggregation and activation of caspases. Proc Natl Acad Sci U S A 96:8699–8704PubMed
61.
Landowski TH, Shain KH, Oshiro MM, Buyuksal I, Painter JS, Dalton WS (1999) Myeloma cells selected for resistance to CD95-mediated apoptosis are not cross-resistant to cytotoxic drugs: evidence for independent mechanisms of caspase activation. Blood 94:265–274PubMed
62.
Eischen CM, Kottke TJ, Martins LM, Basi GS, Tung JS, Earnshaw WC, Leibson PJ, Kaufmann SH (1997) Comparison of apoptosis in wild-type and Fas-resistant cells: chemotherapy-induced apoptosis is not dependent on Fas/Fas ligand interactions. Blood 90:935–943PubMed
63.
Villunger A, Egle A, Kos M, Hartmann BL, Geley S, Kofler R, Greil R (1997) Drug-induced apoptosis is associated with enhanced Fas (Apo-1/CD95) ligand expression but occurs independently of Fas (Apo-1/CD95) signaling in human T-acute lymphatic leukemia cells. Cancer Res 57:3331–3334PubMed
64.
Yeh WC, Pompa JL, McCurrach ME, Shu HB, Elia AJ, Shahinian A, Ng M, Wakeham A, Khoo W, Mitchell K, El-Deiry WS, Lowe SW, Goeddel DV, Mak TW (1998) FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis. Science 279:1954–1958PubMed
65.
Varfolomeev EE, Schuchmann M, Luria V, Chiannilkulchai N, Beckmann JS, Mett IL, Rebrikov D, Brodianski VM, Kemper OC, Kollet O, Lapidot T, Soffer D, Sobe T, Avraham KB, Goncharov T, Holtmann H, Lonai P, Wallach D (1998) Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally. Immunity 9:267–276PubMed
66.
Hakem R, Hakem A, Duncan GS, Henderson JT, Woo M, Soengas MS, Elia A, de la Pompa JL, Kagi D, Khoo W, Potter J, Yoshida R, Kaufman SA, Lowe SW, Penninger JM, Mak TW (1998) Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell 94:339–352PubMed
67.
Yoshida H, Kong YY, Yoshida R, Elia AJ, Hakem A, Hakem R, Penninger JM, Mak TW (1998) Apaf1 is required for mitochondrial pathways of apoptosis and brain development. Cell 94:739–750PubMed
68.
Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin KM, Krammer PH, Peter ME (1998) Two CD95 (APO-1/Fas) signaling pathways. EMBO J 17:1675–1687PubMed
69.
Joseph B, Ekedahl J, Sirzen F, Lewensohn R, Zhivotovsky B (1999) Differences in expression of pro-caspases in small cell and non-small cell lung carcinoma. Biochem Biophys Res Commun 262:381–387CrossRefPubMed
70.
Janicke RU, Sprengart ML, Wati MR, Porter AG (1998) Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. J Biol Chem 273:9357–9360PubMed
71.
Yang XH, Sladek TL, Liu X, Butler BR, Froelich CJ, Thor AD (2001) Reconstitution of caspase 3 sensitizes MCF-7 breast cancer cells to doxorubicin- and etoposide-induced apoptosis. Cancer Res 61:348–354PubMed
72.
Teitz T, Wei T, Valentine MB, Vanin EF, Grenet J, Valentine VA, Behm FG, Look AT, Lahti JM, Kidd VJ (2000) Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN. Nat Med 6:529–535PubMed
73.
Fulda S, Kufer MU, Meyer E, van Valen F, Dockhorn-Dworniczak B, Debatin KM (2001) Sensitization for death receptor- or drug-induced apoptosis by re-expression of caspase-8 through demethylation or gene transfer. Oncogene 20:5865–5877PubMed
74.
Droin N, Dubrez L, Eymin B, Renvoize C, Breard J, Dimanche-Boitrel MT, Solary E (1998) Upregulation of CASP genes in human tumor cells undergoing etoposide-induced apoptosis. Oncogene 16:2885–2894CrossRefPubMed
75.
Fulda S, Debatin KM (2003) IFN γ sensitizes for apoptosis by upregulating caspase-8 expression through the Stat1 pathway. Oncogene (in press)
76.
Micheau O, Hammann A, Solary E, Dimanche-Boitrel MT (1999) STAT-1-independent upregulation of FADD and procaspase-3 and -8 in cancer cells treated with cytotoxic drugs. Biochem Biophys Res Commun 256:603–607CrossRefPubMed
77.
78.
Cheng EH, Wei MC, Weiler S, Flavell RA, Mak TW, Lindsten T, Korsmeyer SJ (2001) BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol Cell 8:705–711PubMed
79.
Minn AJ, Rudin CM, Boise LH, Thompson CB (1995) Expression of bcl-xL can confer a multidrug resistance phenotype. Blood 86:1903–1910PubMed
80.
Campos L, Rouault JP, Sabido O, Oriol P, Roubi N, Vasselon C, Archimbaud E, Magaud JP, Guyotat D (1993) High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. Blood 81:3091–3096PubMed
81.
Bargou RC, Daniel PT, Mapara MY, Bommert K, Wagener C, Kallinich B, Royer HD, Dorken B (1995) Expression of the bcl-2 gene family in normal and malignant breast tissue: low bax-alpha expression in tumor cells correlates with resistance towards apoptosis. Int J Cancer 60:854–859PubMed
82.
Prokop A, Wieder T, Sturm I, Essmann F, Seeger K, Wuchter C, Ludwig WD, Henze G, Dorken B, Daniel PT (2000) Relapse in childhood acute lymphoblastic leukemia is associated with a decrease of the Bax/Bcl-2 ratio and loss of spontaneous caspase-3 processing in vivo. Leukemia 14:1606–1613CrossRefPubMed
83.
Sturm I, Kohne CH, Wolff G, Petrowsky H, Hillebrand T, Hauptmann S, Lorenz M, Dorken B, Daniel PT (1999) Analysis of the p53/BAX pathway in colorectal cancer: low BAX is a negative prognostic factor in patients with resected liver metastases. J Clin Oncol 17:1364–1374PubMed
84.
Sturm I, Petrowsky H, Volz R, Lorenz M, Radetzki S, Hillebrand T, Wolff G, Hauptmann S, Dorken B, Daniel PT (2001) Analysis of p53/BAX/p16(ink4a/CDKN2) in esophageal squamous cell carcinoma: high BAX and p16(ink4a/CDKN2) identifies patients with good prognosis. J Clin Oncol 19:2272–2281PubMed
85.
Deveraux QL, Reed JC (1999) IAP family proteins-suppressors of apoptosis. Genes Dev 13:239–252PubMed
86.
Holcik M, Korneluk RG (2001) XIAP, the guardian angel. Nat Rev Mol Cell Biol 7:550–556CrossRef
87.
Reed JC, Bischoff JR (2000) BIRinging chromosomes through cell division--and survivin’ the experience. Cell 102:545–548PubMed
88.
Tamm I, Kornblau SM, Segall H, Krajewski S, Welsh K, Kitada S, Scudiero DA, Tudor G, Qui YH, Monks A, Andreeff M, Reed JC (2000) Expression and prognostic significance of IAP-family genes in human cancers and myeloid leukemias. Clin Cancer Res 6:1796–1803
89.
Adida C, Recher C, Raffoux E, Daniel MT, Taksin AL, Rousselot P, Sigaux F, Degos L, Altieri DC, Dombret H (2000) Expression and prognostic significance of survivin in de novo acute myeloid leukaemia. Br J Haematol 111:196–203CrossRefPubMed
90.
Adida C, Berrebi D, Peuchmaur M, Reyes-Mugica M, Altieri DC (1998) Anti-apoptosis gene, survivin, and prognosis of neuroblastoma. Lancet 351:882–883PubMed
91.
Li J, Feng Q, Kim JM, Schneiderman D, Liston P, Li M, Vanderhyden B, Faught W, Fung MF, Senterman M, Korneluk RG, Tsang BK (2001) Human ovarian cancer and cisplatin resistance: possible role of inhibitor of apoptosis proteins. Endocrinology 142:370–380PubMed
92.
Datta R, Oki E, Endo K, Biedermann V, Ren J, Kufe D (2000) XIAP regulates DNA damage-induced apoptosis downstream of caspase-9 cleavage. J Biol Chem 2000275:31733–31738CrossRef
93.
Suliman A, Lam A, Datta R, Srivastava RK (2000) Intracellular mechanisms of TRAIL: apoptosis through mitochondrial-dependent and -independent pathways. Oncogene 20:2122–2133CrossRef
94.
Fulda S, Wick W, Debatin K-M (2002) Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. Nat Med 8(8):808–815PubMed
95.
Tamm I, Trepel M, Cardó-Vila M, Sun Y, Welsh K, Cabezas E, Swatterthwait A, Arap W, Reed JC (2003) Peptides teargeting caspase inhibitors. J Bio Chem 278(16):14401–14405CrossRef
96.
Mayo MW, Baldwin AS (2000) The transcription factor NF-kB: control of oncogenesis and cancer therapy resistance. Biochim Biophys Acta 1470:M55–M62CrossRefPubMed
97.
Herr I, Posovszky C, Di Marzio L, Cifone MG, Böhler T, Debatin K-M (2000) Autoamplification of apoptosis following ligation of CD95L, TRAIL- and TNF-α. Oncogene 19(37):4255–4262CrossRefPubMed
98.
Herr I, Wilhelm D, Böhler T, Angel P, Debatin K-M (1999) JNK/SAPK activity is not sufficient for anticancer therapy-induced apoptosis involving CD95L, TRAIL, and TNF-α. Int J Cancer 80:417–424CrossRefPubMed
99.
Herr I, Wilhelm D, Meyer E, Jeremias I, Angel P, Debatin K-M (1999) JNK/SAPK activity contributes to TRAIL-induced apoptosis. Cell Death Differ 6:130–135CrossRefPubMed
100.
Herr I, Böhler T, Wilhelm D, Angel P, Debatin K-M (1997) Activation of CD95 (APO-1/Fas) signaling by ceramide mediates cancer therapy-induced apoptosis. EMBO J 16:6200–6208PubMed
Metadata
Title
Apoptosis pathways in cancer and cancer therapy
Author
Klaus-Michael Debatin
Publication date
01-03-2004
Publisher
Springer-Verlag
Published in
Cancer Immunology, Immunotherapy / Issue 3/2004
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-003-0474-8

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