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.

l-Asparaginase-mediated downregulation of c-Myc promotes 1,25(OH)2D3-induced myeloid differentiation in acute myeloid leukemia cells

“…In an earlier study, we reported that Asn synthetase (ASNS), which controls the intracellular level of Asn by controlling the synthesis of this amino acid, was downregulated in HL‐60 cells undergoing myeloid differentiation . This finding correlates with the observations that have been reported by other research groups .…”

Parthenolide as Cooperating Agent for Anti-Cancer Treatment of Various Malignancies

“…ATRA forced promyelocytic leukemia cells to differentiate and inhibited their proliferation [151]. PN increased ATRA-induced HL-60 cell differentiation into a granulocytic lineage involving activation of PKC, ERK2, JNK and PI3-K and downregulation of asparagine synthetase expression [152,153]. Close association between enhancement of cell differentiation and inhibition of NF-κB DNA-binding activity by PN was shown [152].…”