Synergistic induction of ICAM-1 expression by cisplatin and 5-fluorouracil in a cancer cell line via a NF-kappaB independent pathway.
Cisplatin (CDDP) and 5-fluorouracil (5-FU) are common anti-tumour agents, and the anti-tumour effect of CDDP and 5-FU are synergistically enhanced by combined treatment. To clarify the mechanisms of this synergism, we examined the effect of CDDP and 5-FU on the expression of cell adhesion molecules involved in recognition of cancer cells by T lymphocytes. When NA cells, a squamous cell carcinoma cell line, were exposed to CDDP and 5-FU for 18 h, the expression of intercellular adhesion molecule-1 (ICAM-1) was synergistically induced, whereas CDDP or 5-FU alone did not induce the expression of ICAM-1, as determined by flow cytometry. Expression of ICAM-2 and ICAM-3, which are recognized by the same counter receptor on T-cells, were not up-regulated by CDDP and 5-FU. RT-PCR analysis showed that the induction of ICAM-1 on NA cells might be due to transcriptional induction of ICAM-1 mRNA. Treatment with genistein, a protein tyrosine kinase (PTK) inhibitor, inhibited the induction of ICAM-1 on NA cells by CDDP and 5-FU, whereas staurosporin, a protein kinase C inhibitor, did not. Although CDDP and 5-FU induced binding at the nuclear factor kappa B (NF-kappaB) site in the ICAM-1 promoter, pretreatment with genistein did not prevent CDDP and 5-FU-induced binding at the NF-kappaB site. Moreover, a NF-kappaB nuclear translocation inhibitor did not inhibit the induction of ICAM-1 expression by treatment with CDDP and 5-FU. The synergistic effect of CDDP and 5-FU was not specific to NA cells, since ICAM-1 was synergistically induced by CDDP and 5-FU on HSC-4 cells, a squamous cell carcinoma cell line. These findings indicate that treatment with CDDP and 5-FU induces ICAM-1 expression by a NF-kappaB independent regulatory mechanism involving PTK.
Takizawa
K
K
Second Department of Oral and Maxillofacial Surgery, School of Dentistry, Showa University, Tokyo, Japan.
Kamijo
R
R
Ito
D
D
Hatori
M
M
Sumitani
K
K
Nagumo
M
M
D015703:Antigens, CD / Q000096:biosynthesis; D000943:Antigens, Differentiation; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002945:Cisplatin / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004357:Drug Synergism; D019040:E-Selectin / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
D015703:Antigens, CD; D000943:Antigens, Differentiation; D015815:Cell Adhesion Molecules; D016207:Cytokines; D019040:E-Selectin; D004791:Enzyme Inhibitors; C065289:ICAM2 protein, human; C483616:ICAM3 protein, human; D016328:NF-kappa B; D012333:RNA, Messenger; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D004247:DNA; D002945:Cisplatin; D005472:Fluorouracil