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Cell type specific involvement of death receptor and mitochondrial pathways in drug-induced apoptosis.
Oncogene. 2001 Mar 01; 20(9):1063-75.O

Abstract

Apoptosis in response to cellular stress such as treatment with cytotoxic drugs is mediated by effector caspases (caspase-3) which can be activated by different initiator pathways. Here, we report on a cell type specific triggering of death receptor and/or mitochondrial pathways upon drug treatment. In type I cells (BJAB), both the receptor and the mitochondrial pathway were activated upon drug treatment, since blockade of either the receptor pathway by overexpression of dominant negative FADD (FADD-DN) or of the mitochondrial pathway by overexpression of Bcl-X(L) only partially inhibited apoptosis. Drug treatment induced formation of a FADD- and caspase-8-containing CD95 death-inducing signaling complex (DISC) in type I cells resulting in activation of caspase-8 as the most apical caspase. In contrast, in type II cells (Jurkat), apoptosis was predominantly controlled by mitochondria, since overexpression of Bcl-2 completely blocked drug-induced apoptosis, while overexpression of FADD-DN had no protective effect. In these cells, caspases including caspase-8 were activated by mitochondria-driven signaling events and no DISC was detected despite expression levels of CD95, FADD and caspase-8 proteins comparable to type I cells. Likewise, drug-induced CD95 aggregation was predominantly found in type I cells. Bid was cleaved prior to mitochondrial alterations in type I cells providing a molecular link between caspase-8 activation and mitochondrial perturbations, whereas in type II cells, Bid was cleaved downstream of mitochondria. Our findings of a cell type specific response to cytotoxic drugs have implications for the identification of molecular parameters for chemosensitivity or resistance in different tumor cells.

Authors+Show Affiliations

University Children's Hospital, Prittwitzstr. 43, D-89075 Ulm, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11314043

Citation

Fulda, S, et al. "Cell Type Specific Involvement of Death Receptor and Mitochondrial Pathways in Drug-induced Apoptosis." Oncogene, vol. 20, no. 9, 2001, pp. 1063-75.
Fulda S, Meyer E, Friesen C, et al. Cell type specific involvement of death receptor and mitochondrial pathways in drug-induced apoptosis. Oncogene. 2001;20(9):1063-75.
Fulda, S., Meyer, E., Friesen, C., Susin, S. A., Kroemer, G., & Debatin, K. M. (2001). Cell type specific involvement of death receptor and mitochondrial pathways in drug-induced apoptosis. Oncogene, 20(9), 1063-75.
Fulda S, et al. Cell Type Specific Involvement of Death Receptor and Mitochondrial Pathways in Drug-induced Apoptosis. Oncogene. 2001 Mar 1;20(9):1063-75. PubMed PMID: 11314043.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cell type specific involvement of death receptor and mitochondrial pathways in drug-induced apoptosis. AU - Fulda,S, AU - Meyer,E, AU - Friesen,C, AU - Susin,S A, AU - Kroemer,G, AU - Debatin,K M, PY - 2000/08/16/received PY - 2000/11/22/revised PY - 2000/11/29/accepted PY - 2001/4/21/pubmed PY - 2001/5/18/medline PY - 2001/4/21/entrez SP - 1063 EP - 75 JF - Oncogene JO - Oncogene VL - 20 IS - 9 N2 - Apoptosis in response to cellular stress such as treatment with cytotoxic drugs is mediated by effector caspases (caspase-3) which can be activated by different initiator pathways. Here, we report on a cell type specific triggering of death receptor and/or mitochondrial pathways upon drug treatment. In type I cells (BJAB), both the receptor and the mitochondrial pathway were activated upon drug treatment, since blockade of either the receptor pathway by overexpression of dominant negative FADD (FADD-DN) or of the mitochondrial pathway by overexpression of Bcl-X(L) only partially inhibited apoptosis. Drug treatment induced formation of a FADD- and caspase-8-containing CD95 death-inducing signaling complex (DISC) in type I cells resulting in activation of caspase-8 as the most apical caspase. In contrast, in type II cells (Jurkat), apoptosis was predominantly controlled by mitochondria, since overexpression of Bcl-2 completely blocked drug-induced apoptosis, while overexpression of FADD-DN had no protective effect. In these cells, caspases including caspase-8 were activated by mitochondria-driven signaling events and no DISC was detected despite expression levels of CD95, FADD and caspase-8 proteins comparable to type I cells. Likewise, drug-induced CD95 aggregation was predominantly found in type I cells. Bid was cleaved prior to mitochondrial alterations in type I cells providing a molecular link between caspase-8 activation and mitochondrial perturbations, whereas in type II cells, Bid was cleaved downstream of mitochondria. Our findings of a cell type specific response to cytotoxic drugs have implications for the identification of molecular parameters for chemosensitivity or resistance in different tumor cells. SN - 0950-9232 UR - https://www.unboundmedicine.com/medline/citation/11314043/Cell_type_specific_involvement_of_death_receptor_and_mitochondrial_pathways_in_drug_induced_apoptosis_ L2 - https://doi.org/10.1038/sj.onc.1204141 DB - PRIME DP - Unbound Medicine ER -