Doxorubicin and selenium cooperatively induce fas signaling in the absence of Fas/Fas ligand interaction.
BACKGROUND
The synergistic effect of doxorubicin and selenium in apoptosis induction in MCF-7 breast cancer cells has been previously reported. Mitochondrial activation of caspase-9 is in part responsible for the synergy. The present study aimed at examining the death receptor pathway in activating caspase-8 by the two-drug combination.


METHODS
We determined the expression of TRAIL and FasL signaling molecules and monitored activated caspase-8 in response to neutralizing/blocking antibodies against ligands/receptors.


RESULTS
Our data suggest that TRAIL signaling might not play a role. With respect to the Fas pathway, it was found that doxorubicin enhanced Fas oligomerization (i.e. activation) independent of FasL-Fas interaction. Selenium, on the other hand, increased the expression of FADD, a key adaptor molecule responsible for recruitment of caspase-8 to the Fas oligomer. The significance of the above changes was confirmed by the detection of considerably more caspase-8 in both the Fas or FADD immunoprecipitate obtained from cells treated with the doxorubicin/selenium combination.


CONCLUSIONS
Doxorubicin and selenium cooperatively activate Fas signaling by targeting key regulatory steps.
Li
Song
S
Department of Cancer Chemoprevention, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Zhou
Yunfei
Y
Dong
Yan
Y
Ip
Clement
C
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D004789:Enzyme Activation; D053222:Fas Ligand Protein / Q000378:metabolism*; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D016566:Organoselenium Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D053218:Receptors, Death Domain / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism*
C505533:FADD protein, human; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; D016566:Organoselenium Compounds; D053218:Receptors, Death Domain; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D019014:fas Receptor; D004317:Doxorubicin; C008493:methylselenic acid; D053181:Caspase 8