A novel retinoic acid receptor (RAR)-selective antagonist inhibits differentiation and apoptosis of HL-60 cells: implications of RARalpha-mediated signals in myeloid leukemic cells.
Retinoic acid (RA) induces HL-60 cells to differentiate terminally into mature granulocytes, which subsequently die by apoptosis. The biological effects of RA are mediated by two distinct families of transcription factors: retinoic acid receptors (RARs) and retinoid X receptors (RXRs). RARs and RXRs form heterodimers and regulate retinoid-mediated gene expression. We have recently developed a novel RAR-selective antagonist (ER27191) which prevents RAR activation by retinoids. Using this RAR-selective antagonist, and RXR and RAR agonist, we demonstrate the RAR-mediated signaling pathway is important for differentiation and apoptosis of myeloid leukemic cells. Simple activation of RXRs is not sufficient to induce apoptosis of the cells. Interestingly, the combination of the RAR-selective antagonist and 9-cis RA resulted in partial differentiation and apoptosis of HL-60 and NB4 cells, whereas the RAR antagonist completely blocked all-trans RA-induced differentiation and apoptosis of the cells. Additional experiments showed that levels of BCL-2 protein decreased during differentiation of myeloid leukemic cells. Furthermore, HL-60 cells transduced with a bcl-2 expression vector showed the same differentiation response to retinoids as did parental HL-60 cells even though apoptosis was inhibited in these bcl-2-transduced cells, suggesting that differentiation and apoptosis are regulated independently in myeloid leukemic cells.
Division of Hematology, Keio University School of Medicine, Tokyo, Japan.
H
H
Ueno
M
M
Kizaki
H
H
Matsushita
A
A
Muto
K
K
Yamato
T
T
Nishihara
T
T
Hida
H
H
Yoshimura
H P
HP
Koeffler
Y
Y
Ikeda
D000077556:Alitretinoin; D000873:Anthracenes / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004351:Drug Resistance; D018922:HL-60 Cells / Q000166:cytology* / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D007951:Leukemia, Myeloid / Q000473:pathology; D007962:Leukocytes / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology
C113597:4-(4,5,7,8,9,10-hexahydro-7,7,10,10-tetramethyl-1-(3-pyridylmethyl)anthra-(1,2-b)pyrrol-3-yl)benzoic acid; D000873:Anthracenes; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D000077556:Alitretinoin; D014212:Tretinoin