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Chemosensitivity of solid tumor cells in vitro is related to activation of the CD95 system
Author(s) -
Fulda Simone,
Los Marek,
Friesen Claudia,
Debatin KlausMichael
Publication year - 1998
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19980330)76:1<105::aid-ijc17>3.0.co;2-b
Subject(s) - fas receptor , apoptosis , cancer research , caspase , intrinsic apoptosis , autocrine signalling , fas ligand , programmed cell death , biology , receptor , biochemistry
We have identified the CD95 system as a key mediator of chemotherapy‐induced apoptosis in leukemia and neuroblastoma cells. Here, we report that sensitivity of various solid tumor cell lines for drug‐induced cell death corresponds to activation of the CD95 system. Upon drug treatment, strong induction of CD95 ligand (CD95‐L) and caspase activity were found in chemosensitive tumor cells (Hodgkin, Ewing's sarcoma, colon carcinoma and small cell lung carcinoma) but not in tumor cells which responded poorly to drug treatment (breast carcinoma and renal cell carcinoma). Blockade of CD95 using F(ab′) 2 anti‐CD95 antibody fragments markedly reduced drug‐induced apoptosis, suggesting that drug‐triggered apoptosis depended on CD95‐L/receptor interaction. Moreover, drug treatment induced CD95 expression, thereby increasing sensitivity for CD95‐induced apoptosis. Drug‐induced apoptosis critically depended on activation of caspases (ICE/Ced‐3‐like proteases) since the broad‐spectrum inhibitor of caspases zVAD‐fmk strongly reduced drug‐mediated apoptosis. The prototype substrate of caspases, poly(ADP‐ribose) polymerase, was cleaved upon drug treatment, suggesting that CD95‐L triggered autocrine/paracrine death via activation of caspases. Our data suggest that chemosensitivity of solid tumor cells depends on intact apoptosis pathways involving activation of the CD95 system and processing of caspases. Our findings may have important implications for new treatment approaches to increase sensitivity and to overcome resistance of solid tumors. Int. J. Cancer 76:105–114, 1998.© 1998 Wiley‐Liss, Inc.