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.
Similar content being viewed by others
References
Debatin KM (1999) The role of the CD95 system in chemotherapy. In: Broxterman HJA (ed) Drug resistance updates. Churchill Livingstone, Edinburgh, pp 85–90
Herr I, Debatin KM (2001) Cellular stress response and apoptosis in cancer therapy. Blood 98:2603–2614
Debatin, KM (1997) Anticancer drugs, programmed cell death and the immune system: defining new roles in an old play. J Natl Cancer Inst 89:750–753
Kaufmann SH, Earnshaw WC (2000) Induction of apoptosis by cancer chemotherapy. Exp Cell Res 256:42–49
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 14:1833–1849
Lowe SW, Lin AW (2000) Apoptosis in cancer. Carcinogenesis 21:485–495
Kaufmann SH, Gores GJ (2000) Apoptosis in cancer: cause and cure. Bioessays 22:1007–1017
Hengartner MO (2000) The biochemistry of apoptosis. Nature 407:770–777
Rich T, Allen RL, Wyllie AH (2000) Defying death after DNA damage. Nature 407:777–783
Leppa S, Bohmann D (1999) Diverse functions of JNK signaling and c-Jun in stress response and apoptosis. Oncogene 18:6158–6162
Davis RJ (2000) Signal transduction by the JNK group of MAP kinases. Cell 103:239–252
Mayo MW, Baldwin AS (2000) The transcription factor NF-kB: control of oncogenesis and cancer therapy resistance. Biochim Biophys Acta 1470:M55–M62
Thornberry N, Lazebnik Y (1998) Caspases: enemies within. Science 281:1312–1316
Los M, Wesselborg S, Schulze-Osthoff K (1999) The role of caspases in development, immunity, and apoptotic signal transduction: lessons from knockout mice. Immunity 10:629–639
Degen WGJ, Pruijn GJM, Raats JMH, van Venrooij WJ (2000) Caspase-dependent cleavage of nucleic acids. Cell Death Differ 7:616–627
Slee EA, Adrain C, Martin SJ (1999) Serial killers: ordering caspase activation events in apoptosis. Cell Death Differ 6:1067–1074
Utz PJ, Anderson P (2000) Life and death decisions: regulation of apoptosis by proteolysis of signaling molecules. Cell Death Differ 7:589–602
Earnshaw WC, Martins LM, Kaufmann SH (1999) Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu Rev Biochem 68:383–424
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 49:5870–5878
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 90:3118–3129
Goyal L (2001) Cell death inhibition: keeping caspases in check. Cell 104:805–808
Reed JC (1999) Dysregulation of apoptosis in cancer. J Clin Oncol 17:2941–2953
Finkel E (1999) Does cancer therapy trigger cell suicide? Science 286:2256–2258
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
Wyllie AH, Golstein P (2000) More than one way to go. Proc Natl Acad Sci U S A 93:11–13
Borner C, Monney L (1999) Apoptosis without caspases: an inefficient molecular guillotine? Cell Death Differ 6:497–507
Johnson DE (2000) Noncaspase proteases in apoptosis. Leukemia 14:1695–1703
Leist M, Jaattela M (2001) Four deaths and a funeral: from caspases to alternative mechanisms. Nat Rev Mol Cell Biol 2:589–598
Ferri KF, Kroemer G (2000) Control of apoptotic DNA degradation. Nat Cell Biol 2:E63–E64
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 476:118–123
Schulze-Osthoff K, Ferrari D, Los M, Wesselborg S, Peter ME (1998) Apoptosis signaling by death receptors. Eur J Biochem 4:439–459
Krammer PH (2000) CD95’s deadly mission in the immune system. Nature 407:789–95
Walczak H, Krammer PH (2000) The CD95 (APO-1/Fas) and the TRAIL (APO-2L) apoptosis systems. Exp Cell Res 256:58–66
Costantini P, Jacotot E, Decaudin D, Kroemer G (2000) Mitochondrion as a novel target of anticancer chemotherapy. J Natl Cancer Inst 92:1042–1053
Kroemer G, Reed JC (2000) Mitochondrial control of cell death. Nat Med 6:513–519
Martinou JC, Green DR (2001) Breaking the mitochondrial barrier. Nat Rev Mol Cell Biol 2:63–67
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 8:613–621
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 102:33–42
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 102:43–53
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 256:27–33
Adrain C, Martin SJ (2001) The mitochondrial apoptosome: a killer unleashed by the cytochrome seas. Trends Biochem Sci 26:390–397
Li LY, Luo X, Wang X (2001) Endonuclease G is an apoptotic DNase when released from mitochondria. Nature 412:95–99
Schimmer AD, Hedley DW, Penn LZ, Minden MD (2001) Receptor- and mitochondrial-mediated apoptosis in acute leukemia: a translational view. Blood 98:3541–3553
Roy S, Nicholson DW (2000) Cross-talk in cell death signaling. J Exp Med 192:21–26
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 2:574–577
Friesen C, Fulda S, Debatin KM (1999) Drugs and the CD95 pathway. Leukemia 13:1854–1858
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
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 76:105–114
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 5:884–893
Fulda S, Susin SA, Kroemer G, Debatin KM (1998) Molecular ordering of apoptosis induced by anticancer drugs in neuroblastoma cells. Cancer Res 58:4453–4460
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 95:301–308
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 20:1063–1075
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 16:6200–6208
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 94:8144–8149
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 188:2033–2045
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 99:403–413
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 1:543–551
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 20:7826–7837
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 61:243–248
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 96:8699–8704
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 94:265–274
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 90:935–943
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 57:3331–3334
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 279:1954–1958
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 9:267–276
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 94:339–352
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 94:739–750
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 17:1675–1687
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 262:381–387
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 273:9357–9360
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 61:348–354
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 6:529–535
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 20:5865–5877
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 16:2885–2894
Fulda S, Debatin KM (2003) IFN γ sensitizes for apoptosis by upregulating caspase-8 expression through the Stat1 pathway. Oncogene (in press)
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 256:603–607
Antonsson B, Martinou JC (2000) The Bcl-2 protein family. Exp Cell Res 256:50–57
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 8:705–711
Minn AJ, Rudin CM, Boise LH, Thompson CB (1995) Expression of bcl-xL can confer a multidrug resistance phenotype. Blood 86:1903–1910
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 81:3091–3096
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 60:854–859
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 14:1606–1613
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 17:1364–1374
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 19:2272–2281
Deveraux QL, Reed JC (1999) IAP family proteins-suppressors of apoptosis. Genes Dev 13:239–252
Holcik M, Korneluk RG (2001) XIAP, the guardian angel. Nat Rev Mol Cell Biol 7:550–556
Reed JC, Bischoff JR (2000) BIRinging chromosomes through cell division--and survivin’ the experience. Cell 102:545–548
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
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 111:196–203
Adida C, Berrebi D, Peuchmaur M, Reyes-Mugica M, Altieri DC (1998) Anti-apoptosis gene, survivin, and prognosis of neuroblastoma. Lancet 351:882–883
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 142:370–380
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 2000275:31733–31738
Suliman A, Lam A, Datta R, Srivastava RK (2000) Intracellular mechanisms of TRAIL: apoptosis through mitochondrial-dependent and -independent pathways. Oncogene 20:2122–2133
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):808–815
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):14401–14405
Mayo MW, Baldwin AS (2000) The transcription factor NF-kB: control of oncogenesis and cancer therapy resistance. Biochim Biophys Acta 1470:M55–M62
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):4255–4262
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 80:417–424
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 6:130–135
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 16:6200–6208
Author information
Authors and Affiliations
Corresponding author
Additional information
This work was presented at the first Cancer Immunology and Immunotherapy Summer School, 8–13 September 2003, Ionian Village, Bartholomeio, Peloponnese, Greece.
Rights and permissions
About this article
Cite this article
Debatin, KM. Apoptosis pathways in cancer and cancer therapy. Cancer Immunol Immunother 53, 153–159 (2004). https://doi.org/10.1007/s00262-003-0474-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00262-003-0474-8