Induction of cyclin-dependent kinase inhibitor, p21WAF1, by treatment with 3,4-dihydro-6-[4-(3,4)-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinoline (vesnarinone) in a human salivary cancer cell line with mutant p53 gene.
It has been found by PCR-SSCP analysis and direct DNA sequencing that a human salivary adenosquamous carcinoma-forming cell line, TYS, has a mutant p53 gene at codon 281Asp-->His. When TYS cells were treated with a differentiation-inducing agent, vesnarinone, cellular proliferation was significantly inhibited on the basis of MTT assay. In addition, it has been found by Northern blotting and/or immunoblotting that expression of p21WAF1 and transforming growth factor-beta (TGF-beta) is up-regulated by treating TYS cells with vesnarinone. TGF-beta 1 alone also induced p21WAF1 expression in TYS cells. Moreover, it has been shown by ELISA that the treatment of TYS cells with vesnarinone results in the enhanced generation of latent TGF-beta 1. The expression of TGF-beta receptor (T beta R), including T beta R-I, T beta R-II and T beta R-III, on TYS cells was detected by affinity cross-linking using 125I-TGF-beta 1 and addition of active TGF-beta 1 into serum-free culture medium inhibited the growth of TYS cells in a concentration-dependent manner. These findings suggest that vesnarinone might directly induce expression of p21WAF1 gene in TYS cells, the product of which may be associated with the inhibition of cell growth and induce differentiation.
Sato
M
M
Second Department of Oral and Maxillofacial Surgery, Tokushima University School of Dentistry, Japan.
Kawamata
H
H
Harada
K
K
Nakashiro
K
K
Ikeda
Y
Y
Gohda
H
H
Yoshida
H
H
Nishida
T
T
Ono
K
K
Kinoshita
M
M
Adachi
M
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D018196:Carcinoma, Adenosquamous / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016158:Genes, p53; D006801:Humans; D009154:Mutation; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011719:Pyrazines; D011804:Quinolines / Q000494:pharmacology*; D012468:Salivary Gland Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D011719:Pyrazines; D011804:Quinolines; D016212:Transforming Growth Factor beta; C041667:vesnarinone