Gene expression profiles in differentiating leukemia cells induced by methyl jasmonate are similar to those of cytokinins and methyl jasmonate analogs induce the differentiation of human leukemia cells in primary culture.
Jasmonates are potent lipid regulators in plants that play pivotal roles in their biological activities. Methyl jasmonate (MJ) is very effective at inducing the myelomonocytic differentiation of human myeloid leukemia HL-60 cells. We examined the gene expression profiles associated with exposure to MJ using cDNA microarrays, and compared the results with those obtained with other inducers of differentiation, such as all-trans retinoic acid (ATRA), 1alpha,25-dihydroxyvitamin D(3) (VD(3)), isopentenyladenine (IPA) and cotylenin A (CN-A). Many genes were upregulated, and only a small fraction was downregulated, upon exposure to the inducers. MJ, IPA and CN-A, but not ATRA or VD(3), immediately induced the expression of mRNA for the calcium-binding protein S100P. The gene expression profile induced by MJ resembled that induced by IPA, suggesting that these inducers share many common signal transduction systems for inducing the differentiation of leukemia cells. Methyl 4,5-didehydrojasmonate was about 30 times more potent than MJ and the natural form of the stereoisomer was more effective than the unnatural isomer. It significantly stimulated both the functional and morphological differentiation of leukemia cells that had been freshly isolated from patients with hematological malignancies. Jasmonate derivatives may be promising therapeutic agents for differentiation therapy of leukemia.
Tsumura
H
H
Department of Life Science, Shimane University School of Medicine, Izumo, Shimane, Japan.
Akimoto
M
M
Kiyota
H
H
Ishii
Y
Y
Ishikura
H
H
Honma
Y
Y
D000085:Acetates / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D003517:Cyclopentanes / Q000494:pharmacology*; D003583:Cytokinins / Q000494:pharmacology*; D004952:Esters / Q000494:pharmacology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D018922:HL-60 Cells; D019337:Hematologic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D006801:Humans; D007541:Isopentenyladenosine / Q000494:pharmacology; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D054883:Oxylipins / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000085:Acetates; D003517:Cyclopentanes; D003583:Cytokinins; D004952:Esters; D054883:Oxylipins; C519297:methyl 4,5-didehydrojasmonate; C001478:N(6)-(delta(2)-isopentenyl)adenine; D007541:Isopentenyladenosine; C072239:methyl jasmonate