title: Analysis of gene profiles involved in the enhancement of all-trans retinoic acid-induced HL-60 cell differentiation by sesquiterpene lactones identifies asparagine synthetase as a novel target for differentiation-inducing therapy.
abstract: All-trans retinoic acid (ATRA) is one of the most useful drugs in the treatment for acute promyelocytic leukemia (APL), but its adverse effects, which include drug resistance and hypercalcemia are obstacles to achieving complete remission. Our previous study showed that some sesquiterpene lactones (STLs), i.e., helenalin (HE) and parthenolide (PA) but not sclareolide (SC), enhance ATRA-induced differentiation of HL-60 APL cells with no unexpected effects, but the precise mechanism on underlying this synergism is not yet fully understood. In this study, we investigated the distinctive transcriptional profile of cells treated with effective STL compounds, which were identified by comparing the profile with that of cells treated with SC. Genome-wide approaches using cDNA microarrays showed that co-treatment with the differentiation-enhancing STLs HE and PA maximized the transcriptional variation regulated by the suboptimal concentration of ATRA in HL-60 cells. Of the genes of interest, asparagine synthetase was remarkably downregulated by ATRA co-treated with either HE or PA, but not with SC. In an additional analysis for the role of asparagine synthetase, ATRA-mediated HL-60 cell differentiation was enhanced when asparagine in the culture media was depleted by an addition of L-asparaginase, indicating that downregulation of asparagine synthetase gene expression may be involved in the enhanced cell differentiation by STL compounds. These results provide useful insight into differentiation-inducing therapy in the treatment of leukemia.
authors.affiliation: Department of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
authors.forename: Ju Han
authors.initials: JH
authors.lastname: Song
authors.affiliation: Department of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
authors.forename: Kyung-Min
authors.initials: KM
authors.lastname: Cho
authors.affiliation: Division of Molecular and Life Science and GenoCheck Co. Ltd., Hanyang University, Ansan 426-791, Republic of Korea.
authors.forename: Seung Yong
authors.initials: SY
authors.lastname: Hwang
authors.affiliation: Genome Research Center for Hematopoietic Diseases, Chonnam National University Hwasun Hospital, Hwasun 519-809, Republic of Korea.
authors.forename: Hyeoung-Joon
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
authors.forename: Tae Sung
authors.initials: TS
authors.lastname: Kim
mesh_terms: D001216:Asparagine / Q000378:metabolism; D001217:Aspartate-Ammonia Ligase / Q000096:biosynthesis / Q000235:genetics*; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D003470:Culture Media; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D018168:Receptors, Retinoic Acid / Q000235:genetics* / Q000378:metabolism; D012717:Sesquiterpenes / Q000008:administration & dosage; D045789:Sesquiterpenes, Guaiane; D014212:Tretinoin / Q000008:administration & dosage
chemical_list: D003470:Culture Media; D018168:Receptors, Retinoic Acid; D012717:Sesquiterpenes; D045789:Sesquiterpenes, Guaiane; C002669:parthenolide; C001329:helenalin; D014212:Tretinoin; D001216:Asparagine; D001217:Aspartate-Ammonia Ligase