title: Sphingosine 1-phosphate antagonizes the effect of all-trans retinoic acid (ATRA) in a human colon cancer cell line by modulation of RARβ expression.
abstract: All-trans retinoic acid (ATRA) is a promising therapeutic agent, but exhibits low efficacy against human cancers. We investigated the effect of sphingosine-1-phosphate (S1P) on ATRA activity in human colon cancer HT-29 cells. S1P antagonized ATRA activity on HT-29 cell proliferation and retinoic acid receptor beta (RARβ) expression. S1P treatment or transient co-transfection with SphK2 expression vector antagonized ATRA-induced RARβ promoter activity. Proteasome inhibition prevented S1P-induced modulation of ATRA activity. Overall, S1P antagonized ATRA's inhibitory effects by down-regulating RARβ expression, likely via the proteasome-dependent pathway. Decreasing S1P production or inhibiting SphK2 activity could enhance the efficacy of retinoids in cancer treatments.
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Jinan, China; Department of Bioengineering, School of Life Science, Yan Tai University, Shandong, China.
authors.forename: De-Fu
authors.initials: DF
authors.lastname: Sun
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Calgary and Calgary Laboratory Services, Calgary, Alberta, Canada.
authors.forename: Zu-Hua
authors.initials: ZH
authors.lastname: Gao
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Jinan, China.
authors.forename: Hui-Ping
authors.initials: HP
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Jinan, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Jinan, China. Electronic address: qxj@sdu.edu.cn.
authors.forename: Xian-Jun
authors.initials: XJ
authors.lastname: Qu
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics; D015536:Down-Regulation; D019073:HT29 Cells; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008246:Lysophospholipids / Q000494:pharmacology*; D061988:Proteasome Inhibitors; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014212:Tretinoin / Q000037:antagonists & inhibitors* / Q000494:pharmacology
chemical_list: D007976:Leupeptins; D008246:Lysophospholipids; D061988:Proteasome Inhibitors; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; C060506:sphingosine 1-phosphate; D014212:Tretinoin; D013110:Sphingosine; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde