Cell type specific involvement of death receptor and mitochondrial pathways in drug-induced apoptosis
Authors: K M Debatin
S A Susin
C Friesen
G Kroemer
S Fulda
E Meyer
Journal: Oncogene (2001)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Apoptosis; Caspases; Death receptor; Mitochondrial pathway; Drug treatment
Affiliations: University Children's Hospital, Prittwitzstr. 43, D-89075 Ulm, Germany.

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. 

Retracted: No

PubPeer comments:
 In Figure 3C, two of the Western blots seem to have been duplicated, modified and presented as something else in the same figure (blue and green marking). Furthermore it looks like one of the blots (p-JNK) has one more lane than the other corresponding blots. In Figure 7C, it is difficult to see how the zoomed in micrographs to the right are related to the original micrograph to the left. In Figure 7E, the green staining does not correspond to the green staining in the merged micrograph. ![file] , 
 We have checked the accuracy of our data. The blots, cropped images are corrected and related. We have submitted the original data to JCI, which can be obtained from the editorial upon reasonable request. For example, regarding the western blots in Figure 3C, we have attached the original images as below. We sometimes striped the membrane and re-blot using the antibody that targets another protein, so that the bubble appears at the same location. In Figure 7C, the upper black box relates to the zoomed image on the right (autophagosomes), the lower black box relates to the zoomed image in the middle, we will pay attention in the future to avoid such confusion. Thank you for your interest in our research paper. ![file] ![](http: ) ![file] ,