Sensitivity of prostate cells to TRAIL-induced apoptosis increases with tumor progression: DR5 and caspase 8 are key players.
BACKGROUND
As advanced prostate cancers are resistant to currently available chemotherapies, we evaluated the cytotoxic effect of TNF-related apoptosis-inducing ligand (TRAIL) and characterized the involvement of its five receptors DR4, DR5, DcR1, DcR2, and osteoprotegerin (OPG) and of the death-inducing signaling complex (DISC)-forming proteins caspase 8 and c-FLIP in prostate cell lines.


METHODS
We used six prostate cell lines, each corresponding to a particular stage in prostate tumorigenesis, and analyzed TRAIL sensitivity in relation to TRAIL receptors' expression.


RESULTS
TRAIL sensitivity was correlated with tumor progression and DR5 expression levels and apoptosis was exclusively mediated by DR5. DcR2 was significantly more abundant in tumor cells than in non-neoplastic ones and may contribute to partial resistance to TRAIL in some prostate tumor cells. Conversely, non-tumoral cells secreted high levels of OPG, which can protect them from apoptosis. Finally, caspase 8 expression levels were as DR5 directly correlated to TRAIL sensitivity in prostate tumor cells.


CONCLUSIONS
TRAIL-induced apoptosis is closely related to the balanced expression of its different receptors in prostate cancer cells and their modulation could be of potential clinical value for advanced tumor treatment.
GERHM-INSERM U625, IFR140 GFAS, Université de Rennes I, Rennes cedex, France.
Vincent
V
Hesry
Claire
C
Piquet-Pellorce
Marion
M
Travert
Ludovic
L
Donaghy
Bernard
B
Jégou
Jean-Jacques
JJ
Patard
Thierry
T
Guillaudeux
D000728:Androgens / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053181:Caspase 8; D020169:Caspases / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D053418:Death Domain Receptor Signaling Adaptor Proteins; D018450:Disease Progression; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000235:genetics / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology; D008297:Male; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D009367:Neoplasm Staging; D053244:Osteoprotegerin; D011467:Prostate / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D053221:TNF-Related Apoptosis-Inducing Ligand; D053319:Tumor Necrosis Factor Decoy Receptors; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000728:Androgens; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D053418:Death Domain Receptor Signaling Adaptor Proteins; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C451501:TNFRSF10D protein, human; C506030:TNFRSF11B protein, human; C505653:TNFSF10 protein, human; D053319:Tumor Necrosis Factor Decoy Receptors; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases