CD95 promotes tumour growth.
CD95 (also called Fas and APO-1) is a prototypical death receptor that regulates tissue homeostasis mainly in the immune system through the induction of apoptosis. During cancer progression CD95 is frequently downregulated or cells are rendered apoptosis resistant, raising the possibility that loss of CD95 is part of a mechanism for tumour evasion. However, complete loss of CD95 is rarely seen in human cancers and many cancer cells express large quantities of CD95 and are highly sensitive to CD95-mediated apoptosis in vitro. Furthermore, cancer patients frequently have elevated levels of the physiological ligand for CD95, CD95L. These data raise the possibility that CD95 could actually promote the growth of tumours through its non-apoptotic activities. Here we show that cancer cells in general, regardless of their CD95 apoptosis sensitivity, depend on constitutive activity of CD95, stimulated by cancer-produced CD95L, for optimal growth. Consistently, loss of CD95 in mouse models of ovarian cancer and liver cancer reduces cancer incidence as well as the size of the tumours. The tumorigenic activity of CD95 is mediated by a pathway involving JNK and Jun. These results demonstrate that CD95 has a growth-promoting role during tumorigenesis and indicate that efforts to inhibit its activity rather than to enhance it should be considered during cancer therapy.
Chen
Lina
L
The Ben May Department for Cancer Research, The University of Chicago, 924 E 57th Street, Chicago, Illinois 60637, USA.
Park
Sun-Mi
SM
Tumanov
Alexei V
AV
Hau
Annika
A
Sawada
Kenjiro
K
Feig
Christine
C
Turner
Jerrold R
JR
Fu
Yang-Xin
YX
Romero
Iris L
IL
Lengyel
Ernst
E
Peter
Marcus E
ME
D000818:Animals; D017209:Apoptosis; D018269:Carcinoma, Endometrioid / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D053222:Fas Ligand Protein / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D022781:Hepatocytes / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D019014:fas Receptor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
C491901:FAS protein, human; D053222:Fas Ligand Protein; C491899:Fas protein, mouse; D019014:fas Receptor; D048055:Mitogen-Activated Protein Kinase 8