title: Ectopic p21sdi1 gene transfer induces retinoic acid receptor beta expression and sensitizes human cancer cells to retinoid treatment.
abstract: The biological effects of retinoic acid (RA) are mediated by nuclear retinoic acid receptors (RARs) that function as ligand-activated transcriptional factors. The response of human cancer cells to RA is known to be associated with the expression of RARbeta. Recent studies have demonstrated that the loss of RARbeta expression is involved in the development of a variety of human malignancies. We show that recombinant adenovirus-mediated p21(sdi1) gene transfer enhances RARbeta mRNA expression as well as protein expression and induces the sensitivity to all-trans RA (ATRA) in human cancer cells. Semi-quantitative reverse transcription-polymerase chain reaction analysis demonstrated that infection with adenovirus carrying human p21(sdi1) gene (Ad5CMV-p21), which encodes a cyclin-dependent kinase inhibitor, induced RARbeta mRNA and protein expression in H1299 human non-small cell lung cancer cells and DLD-1 human colorectal cancer cells. We also found that exogenous introduction of the p21(sdi1) gene transcriptionally activated the upstream promoter function of the RARbeta gene. Treatment with 1 microM of ATRA showed no significant inhibitory effects on the growth of H1299 and DLD-1 cells; after Ad5CMV-p21 infection, however, cells underwent apoptosis with ATRA treatment at the same concentration, suggesting that p21(sdi1) gene transfer sensitized H1299 and DLD-1 cells, presumably, through RARbeta upregulation. We also demonstrated the efficacy of intratumoral injection of Ad5CMV-p21 in combination with systemic administration of ATRA in a nude mice xenograft model. Our results indicate that recombinant adenovirus-mediated p21(sdi1) gene transfer could be potentially useful for the local induction of RA sensitivity in human premalignant and malignant lesions lacking appropriate RARbeta expression.
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan.
authors.forename: Fuminori
authors.initials: F
authors.lastname: Teraishi
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Kadowaki
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Tango
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kawashima
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Umeoka
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kagawa
authors.forename: Noriaki
authors.initials: N
authors.lastname: Tanaka
authors.forename: Toshiyoshi
authors.initials: T
authors.lastname: Fujiwara
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics* / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D015870:Gene Expression; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D012333:RNA, Messenger / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014212:Tretinoin / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D017931:DNA Primers; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; D014212:Tretinoin