Growth inhibitory effects of interferon-beta but not interferon-alpha on human glioma cells: correlation of receptor binding, 2',5'-oligoadenylate synthetase and protein kinase activity.
The antiproliferative effects of human recombinant interferon-alpha (rIFN-alpha A) and interferon-beta (rIFN-beta ser) were assessed in vitro against seven human glioma cell lines. Further analysis of one of these lines (EFC-2) in response to rIFN-alpha A demonstrated a minimum growth inhibition by day 6 of treatment, whereas a 50% inhibition of cell growth was observed with a dose of 50 U/ml of IFN-beta ser. No significant growth inhibition was seen by rIFN-alpha A at doses up to 500 U/ml. Addition of rIFN-alpha A to rIFN-beta ser-treated EFC-2 cells neither suppressed nor augmented the antiproliferative response to IFN-beta ser. The binding of 125I-labeled rIFN-alpha A or 125I-labeled rIFN-beta ser to EFC-2 cells was inhibited competitively by increasing concentrations of either unlabeled rIFN-alpha A or rIFN-beta ser. This suggests that the cellular receptors for both rIFN-alpha A and rIFN-beta ser appear to be intact and appear to bind both agents equally. Furthermore, incubation of EFC-2 cells for 72 h with either rIFN-alpha A or rIFN-beta ser resulted in an increase in 2',5'-oligoadenylate (2-5A) synthetase activity 5-fold with rIFN-alpha A and 50-fold with rIFN-beta ser. Similarly, the 68-kD IFN-induced protein kinase was induced substantially with rIFN-beta ser but only slightly induced with rIFN-alpha A treatment. These results suggest that EFC-2 human glioma cells demonstrate a differential sensitivity in terms of growth inhibition to rIFN-beta ser and to rIFN-alpha A which appears to correlate with a differential induction of both intracellular 2-5A synthetase and protein kinase activity. These results cannot be explained solely on the basis of surface receptor binding of rIFN-alpha A and rIFN-beta ser. These data do suggest that, for human glioma cells in culture, type I IFN receptors may display a subtle architectural variation that allows equivalent binding of both IFN-alpha and IFN-beta ser, but allows an enhanced signal transduction and biological effect only after binding a specific IFN subtype.
Rosenblum
M G
MG
Department of Clinical Immunology and Biological Therapy, University of Texas System Cancer Center, M.D. Anderson Hospital and Tumor Institute, Houston 77030.
Yung
W K
WK
Kelleher
P J
PJ
Ruzicka
F
F
Steck
P A
PA
Borden
E C
EC
D015088:2',5'-Oligoadenylate Synthetase / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism / Q000494:pharmacology*; D000068556:Interferon beta-1a; D000068576:Interferon beta-1b; D016899:Interferon-beta; D011494:Protein Kinases / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism*; D017471:Receptors, Interferon; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D007370:Interferon Type I; D011971:Receptors, Immunologic; D017471:Receptors, Interferon; D011994:Recombinant Proteins; D000068576:Interferon beta-1b; D016899:Interferon-beta; D011494:Protein Kinases; D015088:2',5'-Oligoadenylate Synthetase; D000068556:Interferon beta-1a