Carcinoembryonic antigen regulation in human colorectal tumor cells by a site-selective cyclic AMP analogue: a comparison with interferon-gamma.
Treatment of human colorectal tumor cells (LS174T, HT-29, and WiDr) with analogues of cyclic AMP (cAMP) (dibutyryl-cAMP and 8-Cl-cAMP) selectively enhances the expression of carcinoembryonic antigen (CEA). Dose and temporal kinetics results revealed that 8-Cl-cAMP was approximately 100-fold more potent than dibutyryl-cAMP for increasing CEA expression. Results demonstrated that 8-Cl-cAMP treatment of LS174T quantitatively increased CEA levels in cell extracts 2-fold, increased anti-CEA monoclonal antibody (MAb) binding to the tumor cell surface, and induced the appearance of CEA-related mRNA transcripts. The findings suggest that 8-Cl-cAMP is capable of regulating CEA expression at transcriptional and/or post-transcriptional levels. Other human tumor cells, as well as normal cell types which do not constitutively express CEA, remained CEA-negative following 8-Cl-cAMP treatment. Moreover, the level of expression of other human tumor antigens as well as antigens of the major histocompatibility complex were not changed by 8-Cl-cAMP treatment, suggesting some selectivity for CEA regulation by this cAMP analogue. In vivo administration of 8-Cl-cAMP to athymic mice bearing LS174T tumor xenografts increased the amount of anti-CEA MAb bound to tumor extracts as well as the tumor localization of a radionuclide-conjugated anti-CEA MAb. The results indicate that 8-Cl-cAMP can selectively upregulate CEA expression on human colorectal tumor cells in vitro and in vivo. Interestingly, IFN-gamma treatment of the LS174T cells fails to enhance or induce expression of CEA or any of the histocompatibility leukocyte antigens. Thus, 8-Cl-cAMP treatment regulates CEA expression through another cellular pathway which may involve cAMP-dependent protein kinase.
Guadagni
F
F
Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Tortora
G
G
Roselli
M
M
Clair
T
T
Cho-Chung
Y S
YS
Schlom
J
J
Greiner
J W
JW
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003994:Bucladesine / Q000494:pharmacology*; D002272:Carcinoembryonic Antigen / Q000032:analysis / Q000096:biosynthesis*; D002460:Cell Line; D003110:Colonic Neoplasms / Q000276:immunology*; D015179:Colorectal Neoplasms / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D015395:Histocompatibility Antigens Class I / Q000032:analysis / Q000096:biosynthesis; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D008819:Mice, Nude; D011863:Radioimmunoassay; D011994:Recombinant Proteins; D012004:Rectal Neoplasms / Q000276:immunology*; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D002272:Carcinoembryonic Antigen; D015395:Histocompatibility Antigens Class I; D011994:Recombinant Proteins; D015124:8-Bromo Cyclic Adenosine Monophosphate; D003994:Bucladesine; D007371:Interferon-gamma; C044258:8-chloro-cyclic adenosine monophosphate