Caspase-8 and its inhibitors in RCCs in vivo: the prominent role of ARC.
Activation of the initiator-caspase, caspase-8 is under tight control of multiple antiapoptotic regulators including ARC, cFlip(S), cFlip(L) and PED/PEA-15. Since there is little data regarding the expression of caspase-8 and its antiapoptotic regulators in human tumours in vivo, we analysed their expression in renal cell carcinomas (RCCs) to identify which of these genes might be crucial for the well known impaired apoptosis and--as a result--resistance towards chemotherapy and ionizing radiation of RCCs. Caspase-8, cFlip(S), cFlip(L) and PED/PEA-15 mRNA expression was significantly increased only in early stages of RCCs compared to non-neoplastic renal tissue. In contrast, ARC mRNA expression was significantly increased in RCCs of all stages without differences between the tumour stages and grades. Importantly, the relative mRNA expression ratio between ARC and caspase-8 was significantly increased during carcinogenesis and tumour progression. In contrast, the relative mRNA expression ratio between cFlip(S), cFlip(L) or PED/PEA-15 and caspase-8 remained constant during all tumour stages. In conclusion, our analysis revealed that ARC is the only caspase-8 inhibiting regulator being constantly overexpressed in RCCs. Furthermore, the balance between antiapoptotic ARC and proapoptotic caspase-8 is the only one to be disturbed during carcinogenesis and tumour progression of RCCs. This inhibition of Caspase-8 might therefore be one example for the multiple antiapoptotic functions of ARC in RCCs possibly contributing to the marked resistance of RCCs towards radio- and chemotherapy and reflects a shift of gene expression towards a more antiapoptotic context in RCCs.
Institute of Pathology, Heinrich-Heine University Hospital, Moorenstrasse 5, 40225 Duesseldorf, Germany, seb.heikaus@gmx.de
Sebastian
S
Heikaus
Tobias
T
Kempf
Csaba
C
Mahotka
Helmut Erich
HE
Gabbert
Uwe
U
Ramp
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D001483:Base Sequence; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053181:Caspase 8 / Q000235:genetics* / Q000378:metabolism; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D017931:DNA Primers / Q000235:genetics; D004789:Enzyme Activation; D005260:Female; D015870:Gene Expression; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D061945:Caspase Inhibitors; D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; C112246:NOL3 protein, human; C092039:PEA15 protein, human; D010750:Phosphoproteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C505530:CASP8 protein, human; D053181:Caspase 8