title: Differentiation-independent retinoid induction of folate receptor type beta, a potential tumor target in myeloid leukemia.
abstract: Folate receptor (FR) type beta is expressed in the myelomonocytic lineage, predominantly during neutrophil maturation and in myeloid leukemias. FR-beta expression was elevated up to 20-fold by all-trans retinoic acid (ATRA) in KG-1 myeloid leukemia cells in a dose-dependent and reversible manner in the absence of terminal differentiation or cell growth inhibition. ATRA also increased FR-beta expression in vitro in myeloid leukemia cells from patient marrow. FR-beta was not up-regulated in KG-1 cells treated with phorbol ester, dexamethasone, 1,25-dihydroxy vitamin D(3), or transforming growth factor beta. ATRA did not induce FR-beta expression in receptor negative cells of diverse origin. The ATRA-induced increase in FR-beta expression in KG-1 cells occurred at the level of messenger RNA synthesis, and in 293 cells containing a stably integrated FR-beta promoter-luciferase reporter construct, ATRA induced expression of the reporter. From experiments using retinoid agonists and antagonists and from cotransfection studies using the FR-beta promoter and expression plasmids for the nuclear receptors retinoic acid receptor (RAR)alpha, RARbeta, or RARgamma, it appears that the retinoid effect on FR-beta expression could be mediated by ligand binding to RARs alpha, beta, or gamma, but not to retinoid X receptors. Furthermore, there was apparent cross-talk between RARalpha and RARgamma selective agonists or antagonists, suggesting a common downstream target for RAR isoforms in inducing FR-beta expression. Thus, blocks in the RARalpha-specific pathway of retinoid-induced differentiation may be bypassed during retinoid induction of FR-beta expression. The results suggest that to facilitate FR-targeted therapies, retinoids may be used to modulate FR-beta expression in myeloid leukemia cells refractory to retinoid differentiation therapy.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Ohio, Toledo, OH, USA.
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.forename: X
authors.initials: X
authors.lastname: Zheng
authors.forename: F G
authors.initials: FG
authors.lastname: Behm
authors.forename: M
authors.initials: M
authors.lastname: Ratnam
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004274:DNA, Recombinant / Q000187:drug effects; D058973:Folate Receptors, GPI-Anchored; D005786:Gene Expression Regulation / Q000187:drug effects; D017261:Glycosylphosphatidylinositols / Q000378:metabolism; D006801:Humans; D007951:Leukemia, Myeloid / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D011401:Promoter Regions, Genetic / Q000187:drug effects; D020033:Protein Isoforms / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface; D018168:Receptors, Retinoic Acid / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014212:Tretinoin / Q000031:analogs & derivatives / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D002352:Carrier Proteins; D004274:DNA, Recombinant; D058973:Folate Receptors, GPI-Anchored; D017261:Glycosylphosphatidylinositols; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D011956:Receptors, Cell Surface; D018168:Receptors, Retinoic Acid; D014212:Tretinoin; D010738:Type C Phospholipases; D043265:Phosphatidylinositol Diacylglycerol-Lyase