Radiation and anticancer drugs can facilitate mitochondrial bypass by CD95/Fas via c-FLIP downregulation.

Abstract

In many tumor cell types, ionizing radiation or DNA-damaging anticancer drugs enhance sensitivity to death receptor-mediated apoptosis, which is of clinical interest. APO010, a form of CD95/Fas ligand is currently in a phase I trial in patients with solid tumors. To analyze the potential of combined modality treatment with APO010, we used p53-mutant Jurkat T leukemic cells, in which the mitochondrial pathway was blocked by Bcl-2 overexpression. These cells were strongly sensitized to APO010 by pretreatment with ionizing - or UV radiation, etoposide, histone deacetylase - or proteasome inhibitors. These stimuli alone did not induce apoptosis in J16-Bcl-2 cells. Sensitization could not be explained by the overruling of mitochondrial resistance imposed by Bcl-2, upregulation of CD95 membrane levels or modulation of inhibitor of apoptosis proteins. Rather, the stimuli commonly downregulated c-FLIP(L/S) protein levels, which was causally related to the sensitization: deliberate c-FLIP(L/S) downregulation by RNA interference largely overruled the capacity of the various stimuli to sensitize Jurkat-Bcl-2 cells to apoptotic execution by APO010. In p53-mutant, Bcl-2 overexpressing HCT-15 colon carcinoma cells, c-FLIP downregulation correlated with sensitization to APO010 for some, but not all stimuli. We conclude that c-FLIP downregulation represents a mechanism by which diverse anticancer regimens can facilitate tumor cell execution by CD95/Fas through the direct pathway of caspase activation.

• Authors: I Verbrugge, C Maas, M Heijkoop, M Verheij, J Borst
• Journal: Cell death and differentiation (Cell Death Differ) Vol. 17 Issue 3 Pg. 551-61 (Mar 2010) ISSN: 1476-5403 [Electronic] England
• PMID: 19798106 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Antineoplastic Agents, Phytogenic
• CASP8 and FADD-Like Apoptosis Regulating Protein
• Fas Ligand Protein
• Proto-Oncogene Proteins c-bcl-2
• Etoposide
• JNK Mitogen-Activated Protein Kinases

Topics

• Antineoplastic Agents (pharmacology)
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• CASP8 and FADD-Like Apoptosis Regulating Protein (genetics, metabolism)
• Cell Line, Tumor (drug effects, radiation effects)
• Clinical Trials, Phase I as Topic
• Down-Regulation
• Etoposide (pharmacology)
• Fas Ligand Protein (genetics, metabolism)
• Humans
• JNK Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Mitochondria (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• RNA Interference