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

Ju Han Song, Seung Hyun Kim, Kyung Min Cho, Seung Yong Hwang, Hyeoung Joon Kim, Tae Sung Kim

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)970-976
Number of pages7
JournalInternational Journal of Oncology
Volume44
Issue number3
DOIs
Publication statusPublished - 2014 Mar 1

Fingerprint

Aspartate-Ammonia Ligase
Sesquiterpenes
HL-60 Cells
Lactones
Tretinoin
Cell Differentiation
Acute Promyelocytic Leukemia
Genes
Down-Regulation
Therapeutics
Asparaginase
Asparagine
Hypercalcemia
Oligonucleotide Array Sequence Analysis
Drug Resistance
Culture Media
Leukemia
Genome
Gene Expression
Pharmaceutical Preparations

Keywords

  • Acute promyelocytic leukemia
  • All-trans retinoic acid
  • Asparagine synthetase
  • Differentiation
  • Sesquiterpene lactone

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

@article{09409d25ec6c4a06a84837f1472c1172,
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.",
keywords = "Acute promyelocytic leukemia, All-trans retinoic acid, Asparagine synthetase, Differentiation, Sesquiterpene lactone",
author = "Song, {Ju Han} and Kim, {Seung Hyun} and Cho, {Kyung Min} and Hwang, {Seung Yong} and Kim, {Hyeoung Joon} and Kim, {Tae Sung}",
year = "2014",
month = "3",
day = "1",
doi = "10.3892/ijo.2013.2241",
language = "English",
volume = "44",
pages = "970--976",
journal = "International Journal of Oncology",
issn = "1019-6439",
publisher = "Spandidos Publications",
number = "3",

}

TY - JOUR

T1 - 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

AU - Song, Ju Han

AU - Kim, Seung Hyun

AU - Cho, Kyung Min

AU - Hwang, Seung Yong

AU - Kim, Hyeoung Joon

AU - Kim, Tae Sung

PY - 2014/3/1

Y1 - 2014/3/1

N2 - 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.

AB - 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.

KW - Acute promyelocytic leukemia

KW - All-trans retinoic acid

KW - Asparagine synthetase

KW - Differentiation

KW - Sesquiterpene lactone

UR - http://www.scopus.com/inward/record.url?scp=84896723200&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84896723200&partnerID=8YFLogxK

U2 - 10.3892/ijo.2013.2241

DO - 10.3892/ijo.2013.2241

M3 - Article

C2 - 24398846

AN - SCOPUS:84896723200

VL - 44

SP - 970

EP - 976

JO - International Journal of Oncology

JF - International Journal of Oncology

SN - 1019-6439

IS - 3

ER -