Promotion of cell differentiation, and suppression of cell growth and cyclooxygenase-2 expression by differentiation-inducing agents in human oral squamous carcinoma SCC25 cells.
We investigated the relationship between cell growth and differentiation and COX-2 expression in oral squamous cell carcinoma (SCC) in vitro and in vivo. Treatment of SCC25 oral squamous carcinoma cells with sodium butyrate (SB) at 0.5-5 mM or all-trans retinoic acid (ATRA) at 3-300 microM inhibited cell growth and induced apoptosis in a dose-dependent manner with concomittant increases in expression of keratin 13, p21WAF1/Cip1 and p27Kip1 and decreases in expression of COX-2. These effects were more pronounced with SB than with ATRA. Injection of SB or ATRA near SCC25-derived tumors in nude mice resulted in inhibition of growth and elevation of differentiation of the tumor accompanied by marked keratinization and increased expression of keratin 13 and decreased expression of COX-2. These results show that the differentiation-inducing agents, particularly SB, suppress growth of oral squamous carcinoma cells through apoptosis and induce cell differentiation possibly through mechanisms involving COX-2, p27Kip1 and/or p21WAF1/Cip1 in vitro and in vivo.
Kuroda
Junko
J
Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine, Hyogo 663-8501, Japan.
Urade
Masahiro
M
Kishimoto
Hiromitsu
H
Noguchi
Kazuma
K
Hashitani
Susumu
S
Sakurai
Kazunari
K
Nishimura
Norihiko
N
Hashimoto-Tamaoki
Tomoko
T
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002087:Butyrates / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051546:Cyclooxygenase 2; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D058610:Isobutyrates; D007633:Keratins / Q000096:biosynthesis; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D012313:RNA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014212:Tretinoin / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D002087:Butyrates; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D017931:DNA Primers; D058610:Isobutyrates; D008565:Membrane Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D014212:Tretinoin; D012313:RNA; D007633:Keratins; C020380:isobutyric acid; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases