Modulation of the antigenic phenotype of human breast carcinoma cells by modifiers of protein kinase C activity and recombinant human interferons.
In the present study we have analyzed the effect of a synthetic protein kinase C (PKC) activator 3-(N-acetylamino)-5-(N-decyl-N-methylamino)-benzyl alcohol (ADMB) and the natural PKC-activating tumor-promoting agents 12-O-tetradecanoylphorbol 13-acetate (TPA) and mezerein on the antigenic phenotype of T47D human breast carcinoma cells. All three agents increased the surface expression of the tumor-associated antigen BCA 225 and various cellular antigens, including HLA class II antigens, intercellular adhesion molecule 1 (ICAM-1) and c-erbB-2. Expression of the same antigens was also upregulated to various extents in T47D cells by recombinant fibroblast (IFN beta) and immune (IFN gamma) interferon. Shedding of BCA 225 from T47D cells was induced by TPA, mezerein, IFN beta and IFN gamma, whereas ADMB did not display this activity. The ability of ADMB, TPA and mezerein to modulate the antigenic phenotype of T47D cells appears to involve a PKC-mediated pathway, since the PKC inhibitor, H-7, eliminates antigenic modulation. In contrast, the ability of IFN beta and IFN gamma to enhance the synthesis, expression and shedding of BCA 225, as well as to enhance HLA class II antigens, c-erbB-2 and ICAM-1 expression, was either unchanged or modestly reduced by simultaneous exposure to H-7. Analysis of steady-state mRNA levels for HLA class I antigens, HLA class II-DR beta antigen, ICAM-1 and c-erbB-2 indicated that the ability of H-7 to inhibit expression of these antigens in TPA-, mezerein- and ADMB-treated cells was not a consequence of a reduction in the steady-state levels of mRNAs for these antigens. The results of the present investigation indicate that the biochemical pathways mediating enhanced antigenic expression in T47D cells induced by TPA, mezerein and the synthetic PKC activator ADMB are different from those induced by recombinant interferons. Furthermore, up-regulation of antigenic expression in T47D cells can occur by a PKC-dependent or a PKC-independent pathway.
Department of Pathology, Columbia University, College of Physicians and Surgeons, New York, New York 10032.
J A
JA
Leon
M C
MC
Gutierrez
H
H
Jiang
A
A
Estabrook
S
S
Waxman
P B
PB
Fisher
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D001592:Benzyl Alcohols / Q000494:pharmacology; D001943:Breast Neoplasms / Q000276:immunology*; D002277:Carcinoma / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000032:analysis; D002455:Cell Division / Q000187:drug effects; D004224:Diterpenes; D005260:Female; D006023:Glycoproteins / Q000032:analysis; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D006801:Humans; D018799:Intercellular Adhesion Molecule-1; D007370:Interferon Type I / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology; D010641:Phenotype; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins; D013729:Terpenes / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D001592:Benzyl Alcohols; D015815:Cell Adhesion Molecules; D004224:Diterpenes; D006023:Glycoproteins; D000949:Histocompatibility Antigens Class II; D018799:Intercellular Adhesion Molecule-1; D007370:Interferon Type I; D007371:Interferon-gamma; D007546:Isoquinolines; D010879:Piperazines; D011493:Protein Kinase C; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins; D013729:Terpenes; D013755:Tetradecanoylphorbol Acetate; C060363:BCA 225 protein, human; C066732:3-(N-acetylamino)-5-(N-decyl-N-methylamino)benzyl alcohol; C011309:mezerein