title: Growth inhibition of cultured human gastric cancer cells by 9-cis-retinoic acid with induction of cdk inhibitor Waf1/Cip1/Sdi1/p21 protein.
abstract: The effect of 9-cis-retinoic acid (9-cis-RA) on the growth of eight gastric cancer cell lines was related to their transcription levels of mRNAs for retinoid receptors. Northern blot analysis showed that seven (TMK-1, MKN-1, -28, -45, -74, HSC-39, KATO-III) out of eight gastric cancer cell lines synthesized mRNAs for retinoic acid receptors (RARs) and retinoid X receptor-alpha (RXR-alpha). MKN-7 cells did not transcribe either RARs or RXR-alpha at the mRNA level although they appeared to have no alterations at the gene level. The growth of all of the cell lines except for MKN-7 cells was inhibited by 1 x 10(-6) M 9-cis-RA. Cell cycle distribution analysis revealed that G0-G1 arrest was not induced by exposure to 9-cis-RA in the sensitive TMK-1 and KATO-III cells or the resistant MKN-7 cells. Interestingly, 9-cis-RA temporarily increased the amount of the cyclin dependent kinase (cdk) inhibitor, Waf1/Cip1/Sdi1/p21 protein, and also reduced the amount of cdk-7, epidermal growth factor receptor (EGFR) and cyclin D1 proteins, followed by reduction in phosphorylation of the product of the retinoblastoma tumor suppressor gene (Rb) in the sensitive TMK-1 cells, but not in the resistant MKN-7 cells. These results suggest that 9-cis-RA has a cytostatic effect on gastric cancer cells that synthesize the receptor molecules through cell cycle regulatory machinery.
authors.affiliation: First Department of Pathology, Hiroshima University School of Medicine, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Naka
authors.forename: H
authors.initials: H
authors.lastname: Yokozaki
authors.forename: T
authors.initials: T
authors.lastname: Domen
authors.forename: K
authors.initials: K
authors.lastname: Hayashi
authors.forename: H
authors.initials: H
authors.lastname: Kuniyasu
authors.forename: W
authors.initials: W
authors.lastname: Yasui
authors.forename: R
authors.initials: R
authors.lastname: Lotan
authors.forename: E
authors.initials: E
authors.lastname: Tahara
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D000077556:Alitretinoin; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis*; D006801:Humans; D012333:RNA, Messenger / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis; D047488:Retinoid X Receptors; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D014157:Transcription Factors / Q000096:biosynthesis; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D000077556:Alitretinoin; D014212:Tretinoin