9-cis and all-trans retinoic acid induce a similar phenotype in human teratocarcinoma cells.
Prior work has shown that all-trans retinoic acid (t-RA) treatment of the human teratocarcinoma (TC) cell line NTERA-2 clone D1 (abbreviated NT2/D1) induces a neuronal phenotype and other cell lineages. This study sought to explore the potential of 9-cis retinoic acid (9-cis RA) as a differentiation-inducing agent of this multipotent cell. Findings reported here show that 9-cis RA induced a phenotype similar to t-RA treatment of NT2/D1 cells. This similarity extended to their effects on the nuclear receptors retinoic acid receptor-beta (RAR-beta) and retinoid X receptor-alpha (RXR-alpha). Both retinoids prominently augmented RAR-beta expression and transactivated a reporter plasmid containing putative RAR response elements (RAREs) with direct repeats separated by five nucleotides (DR5). Both retinoids had no appreciable effect on RXR-alpha expression and both minimally transactivated a reporter plasmid containing putative RXR response elements (RXREs) with direct repeats separated by one nucleotide (DR1). These studies suggest that 9-cis RA and t-RA activate common events during retinoid-mediated NT2/D1 differentiation. This hypothesis was supported by the finding that NT2/D1 cells rendered refractory to t-RA (NT2/D1-R1) were also resistant to 9-cis RA. To discover alterations that could confer retinoid-refractoriness, retinoid receptor expression was examined in NT2/D1-R1 cells. In contrast to NT2/D1, the NT2/D1-R1 cell was found to have reduced RXR-alpha expression at the level of total cellular RNA.(ABSTRACT TRUNCATED AT 250 WORDS)
Kurie
J M
JM
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
Buck
J
J
Eppinger
T M
TM
Moy
D
D
Dmitrovsky
E
E
D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics; D006801:Humans; D009474:Neurons / Q000187:drug effects; D010641:Phenotype; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis; D013237:Stereoisomerism; D018243:Teratocarcinoma / Q000235:genetics*; D014212:Tretinoin / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D018168:Receptors, Retinoic Acid; D014212:Tretinoin