title: Role of death receptor and mitochondrial pathways in conventional chemotherapy drug induction of apoptosis.
abstract: The molecular mechanism underlying chemotherapy-induced apoptosis is often debated because of contradicting reports of its signaling pathway. The focus of this ongoing debate is on the requirement of a death receptor and its role in subsequent activation of caspase-8. Understanding the precise mechanism responsible for apoptosis and identifying molecules targeted by chemotherapy will allow us to develop better therapeutic strategies that target the inherent abnormalities of cancer cells. To show conventional chemotherapy drugs can trigger the caspase cascade, including caspase-8, -9, -3 and DNA fragmentation factor, Jurkat T leukemia cells were treated with cisplatin or etoposide in a dose-dependent and a time-dependent manner. Cisplatin and etoposide all induced apoptosis in wild-type Jurkat T leukemia cells. On the other hand, when a pan-caspase inhibitor zVAD-FMK was pretreated, apoptosis did not occur, indicating that these chemotherapy drugs mediated caspase-dependent apoptosis. However, the chemotherapy drug induction of apoptosis was not inhibited by treatment of zIETD-FMK, a caspase-8 inhibitor. There was no difference in cell death between wild-type and caspase-8 or FADD-deficient Jurkat cells after treatment of chemotherapy drug. In addition, cisplatin-induced apoptosis is abrogated by the overexpression of either Bcl-2 or Bcl-x(L), which diminished changes of mitochondrial membrane potential and decreased the amount of cytochrome c released from mitochondria. Again, cisplatin-induced apoptosis was not diminished by c-FLIP-overexpression, whereas the c-FLIP-overexpressing cells were less sensitive to TRAIL-induced apoptosis than the wild type cells. Therefore, these results indicate that conventional chemotherapy drug-triggered apoptosis is indispensable, and its pathway is independent of the death receptor.
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada T6G 2S2.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.forename: Jin H
authors.initials: JH
authors.lastname: Song
authors.forename: Doyoun K
authors.initials: DK
authors.lastname: Song
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Chunhai
authors.initials: C
authors.lastname: Hao
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D004358:Drug Therapy; D004789:Enzyme Activation; D053200:Fas-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D053218:Receptors, Death Domain / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053200:Fas-Associated Death Domain Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D053218:Receptors, Death Domain; D053221:TNF-Related Apoptosis-Inducing Ligand; D051020:bcl-X Protein; D053181:Caspase 8; D002945:Cisplatin