The epidermal growth factor- and interferon-independent effects of double-stranded RNA in A431 cells.
The human epidermoid carcinoma cell line A431, containing an amplification in the epidermal growth factor (EGF) receptor gene, was examined for its sensitivity to the growth inhibitory effects of synthetic double-stranded RNAs (dsRNAs). Poly(I).poly(C), poly(A).poly(U) and rln.r(C13,U)n at 5 to 100 micrograms/ml produced 20 to 60% growth inhibition, whereas poly(ICLC) produced 40 to 80% growth inhibition at 0.05 to 25 micrograms/ml.Poly(I).poly(C) did not cause the secretion of interferon (IFN) into the medium, and addition of polyclonal antibodies to IFN-alpha and IFN-beta did not block the growth inhibition produced by poly(I).poly(C). Clone 29, which proliferates in response to EGF, and clone 29R, which is sensitive to the growth inhibitory effects of EGF, showed sensitivities to the antiproliferative effects of poly(I).poly(C) similar to those of the parent cell line. Incubation of cell membrane extracts with poly(I).poly(C) or treatment of cells with the dsRNA did not affect EGF receptor tyrosine kinase activity. On the other hand, poly(I).poly(C) produced a dose-dependent induction of (2',5')oligo(A) synthetase activity and degradation of 45S preribosomal RNA and 28S and 18S rRNA. These results indicate that the growth inhibitory properties of poly(I).poly(C) in A431 cells are independent of the action of IFN but are associated with degradation of rRNA, an effect that may be related to the (2',5')oligo(A)-RNase L pathway.
Chapekar
M S
MS
Laboratory of Biological Chemistry, National Cancer Institute, Bethesda, Maryland 20892.
Knode
M C
MC
Glazer
R I
RI
D015088:2',5'-Oligoadenylate Synthetase / Q000378:metabolism; D000227:Adenine Nucleotides / Q000378:metabolism; D004722:Endoribonucleases / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000502:physiology*; D066246:ErbB Receptors / Q000502:physiology; D006801:Humans; D007158:Immunologic Techniques; D007372:Interferons / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism; D009843:Oligoribonucleotides / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D012330:RNA, Double-Stranded / Q000494:pharmacology*; D012335:RNA, Ribosomal / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000227:Adenine Nucleotides; D008565:Membrane Proteins; D009843:Oligoribonucleotides; D010750:Phosphoproteins; D012330:RNA, Double-Stranded; D012335:RNA, Ribosomal; C023505:2',5'-oligoadenylate; D004815:Epidermal Growth Factor; D007372:Interferons; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D015088:2',5'-Oligoadenylate Synthetase; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease