title: Down-regulated RPS3a/nbl expression during retinoid-induced differentiation of HL-60 cells: a close association with diminished susceptibility to actinomycin D-stimulated apoptosis.
abstract: The efficacy of anticancer agents significantly depends on the differential susceptibility of undifferentiated cancer cells and differentiated normal cells to undergo apoptosis. We previously found that enhanced expression of RPS3a/nbl, which apparently encodes a ribosomal protein, seems to prime cells for apoptosis, while suppressing such enhanced expression triggers cell death. The present study found that HL-60 cells induced to differentiate by all-trans retinoic acid did not undergo apoptosis following treatment with actinomycin D whereas undifferentiated HL-60 cells were highly apoptosis-susceptible, confirming earlier suggestions that differentiated cells have diminished apoptosis-susceptibility. Undifferentiated HL-60 cells highly expressed RPS3a/nbl whereas all-trans retinoic acid -induced differentiated cells exhibited markedly reduced levels, suggesting that apoptosis-resistance of differentiated cells could be due to low RPS3a/nbl expression. Down-regulation of enhanced RPS3a/nbl expression was also observed in cells induced to differentiate with the retinoid 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-1- propenyl]benzoic acid without any significant induction of cell death. While down-regulation of RPS3a/nbl expression during differentiation did not apparently induce apoptosis, RPS3a/nbl antisense oligomers triggered death of undifferentiated HL-60 cells, but not of retinoid-induced differentiated cells. It therefore seems that while down-regulation of enhanced RPS3a/nbl expression can induce apoptosis in undifferentiated cells, down-regulation of enhanced RPS3a/nbl expression during differentiation occurs independently of apoptosis, and could be regarded as reverting the primed condition to the unprimed (low RPS3a/nbl) state.
authors.affiliation: Research School of Biological Sciences, The Australian National University, Canberra, ACT.
authors.forename: L
authors.initials: L
authors.lastname: Russell
authors.forename: H
authors.initials: H
authors.lastname: Naora
authors.forename: H
authors.initials: H
authors.lastname: Naora
mesh_terms: D000943:Antigens, Differentiation / Q000187:drug effects / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D053938:DNA Fragmentation; D003609:Dactinomycin / Q000494:pharmacology*; D015536:Down-Regulation; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D019254:Genes, bcl-2; D018922:HL-60 Cells; D006801:Humans; D020320:Oligoribonucleotides, Antisense / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D000943:Antigens, Differentiation; D000970:Antineoplastic Agents; D020320:Oligoribonucleotides, Antisense; D012333:RNA, Messenger; C031016:RPS3A protein, human; D012269:Ribosomal Proteins; D003609:Dactinomycin; D014212:Tretinoin