The combination of IFN-alpha2 and IFN-alpha8 exhibits synergistic antiproliferative activity on renal cell carcinoma (RCC) cell lines through increased binding affinity for IFNAR-2.
Although there are at least 13 interferon-alpha (IFN-alpha) subtypes in humans, interactions between the subtypes remain unknown. To understand IFN-alpha interactions, we examined the antiproliferative activities and the receptor binding affinities of different combinations of IFN-alpha2 and IFN-alpha8 using six renal cell carcinoma (RCC) cell lines. Although IFN-alpha8 was the more potent subtype, synergistic and antagonistic antiproliferative effects were also observed in certain combinations of IFN-alpha2 and IFN-alpha8. To analyze the interactions between IFN-alpha2 and IFN-alpha8, the receptor-binding kinetics of different combinations of IFN-alpha2 and IFN- alpha8 to the IFN-alpha receptors, IFNAR-1 or IFNAR-2, were measured using a surface plasmon resonance-based biosensor. Unexpectedly, the receptor binding kinetics to IFNAR-2 but not to IFNAR-1 were mutually related to antiproliferative activity and increase in the binding speed (K(a)) for IFNAR-2. Moreover, we observed the increased fluorescence intensity (FI) of biotin-labeled IFN-alpha8 to IFNAR-2 by receptor binding inhibition assay with unlabeled IFN-alpha2 but not the other combinations. These findings indicate that the binding manner of IFN-alpha8 for IFNAR-2 is different from that of IFN-alpha2, suggesting that binding of IFN-alpha8 rather than binding of IFN-alpha2 to IFNAR-2 leads to activation and subsequent antiproliferative activity despite the same antiviral activity in RCC.
Tanimoto
Tadao
T
Biomedical Institute, Research Center, Hayashibara Biochemical Laboratories, Inc., Okayama 702-8006, Japan.
Yamamoto
Shigeto
S
Taniai
Madoka
M
Taniguchi
Mutsuko
M
Ariyasu
Harumi
H
Ushio
Chie
C
Aga
Miho
M
Mukai
Yohei
Y
Tsutsumi
Yasuo
Y
Ariyasu
Toshio
T
Ohta
Tsunetaka
T
Fukuda
Shigeharu
S
D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D016898:Interferon-alpha / Q000145:classification / Q000494:pharmacology*; D007700:Kinetics; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism*
C508033:IFNAR2 protein, human; D016898:Interferon-alpha; D053633:Receptor, Interferon alpha-beta