title: CRABP-II- and FABP5-independent all-trans retinoic acid resistance in COLO 16 human cutaneous squamous cancer cells.
abstract: The effect of all-trans retinoic acid (ATRA) on cutaneous squamous cell carcinomas (c-SCC) has been poorly described. Because the imbalance of CRABP-II-mediated anticancer signalling and FABP5-mediated growth-promoting signalling was supposed to be related with ATRA sensitivities of cancer cells, COLO16 human c-SCC cell line was selected to check underlying mechanism leading to ATRA resistance by multiple experimental approaches. The results revealed that COLO 16 cells were resistant to 15 μm ATRA treatment. FABP5 as well as the elements related with CRABP-II signalling (CYP26A1, CYP26B1, CRABP-I, RARα/β/γ and RXRα/β/γ) and with FABP5 signalling (PPARβ/δ) were expressed, but CRABP-II was undetectable in COLO 16 cells. 5-Aza treatment enhanced CRABP-II expression but further bisulfite sequencing PCR-DNA sequencing revealed no methylation in CRABP-II promoter region. Transfection of CRABP-II-expressing plasmids or FABP5 siRNA or both successfully manipulated the level(s) of target gene expression but failed to overcome ATRA resistance in the transfectants. In conclusion, CRABP-II and FABP5 expression were imbalanced in ATRA-resistant COLO 16 cells. 5-Aza-enhanced CRABP-II expression and unmethylation in CRABP-II promoter region suggest the methylation of certain CRABP-II regulatory gene(s) in COLO 16 cells. As neither restoration of CRABP-II expression nor the increased CRABP-II versus FABP5 ratio can overcome ATRA resistance of COLO 16 cells, additional ATRA-resistant mechanism(s) may present in human c-SCCs and COLO 16 cells would be of value in addressing this issue.
authors.affiliation: Liaoning Laboratory of Cancer Genetics and Epigenetics, Department of Cell Biology, Dalian Medical University, Dalian, China.
authors.forename: Nan-Nan
authors.initials: NN
authors.lastname: Chen
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Mo-Li
authors.initials: ML
authors.lastname: Wu
authors.forename: Zhi-Li
authors.initials: ZL
authors.lastname: Liu
authors.forename: Yuan-Shan
authors.initials: YS
authors.lastname: Fu
authors.forename: Qing-You
authors.initials: QY
authors.lastname: Kong
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Chen
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001374:Azacitidine / Q000031:analogs & derivatives; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D019175:DNA Methylation; D000077209:Decitabine; D019008:Drug Resistance, Neoplasm; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism*; D006801:Humans; D047494:PPAR delta / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D000072516:Retinoic Acid 4-Hydroxylase; D012878:Skin Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D014212:Tretinoin / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; C493412:FABP5 protein, human; D050556:Fatty Acid-Binding Proteins; D047494:PPAR delta; D018168:Receptors, Retinoic Acid; C082927:retinoic acid binding protein I, cellular; C082928:retinoic acid binding protein II, cellular; D014212:Tretinoin; D000077209:Decitabine; D003577:Cytochrome P-450 Enzyme System; C000607079:CYP26B1 protein, human; D000072516:Retinoic Acid 4-Hydroxylase; D001374:Azacitidine