Abstract
Background:
Acute myeloid leukemia (AML) recurrence is largely a result of multidrug resistance (MDR). We aimed to examine the role of 14-3-3ζ in AML chemosensitivity using HL-60 and vincristine-resistant HL-60/VCR cells.
Methods:
The effects of 14-3-3ζ siRNA on the growth and cell cycle progression of HL-60 and HL-60/VCR cells were determined. The effect of 14-3-3ζ siRNA on topotecan (TPT)-induced apoptosis was evaluated by several assays.
Results:
Compared to HL-60 cells, HL-60/VCR cells had increased 14-3-3ζ mRNA and protein expression. Increased mdr-1 mRNA as well as mdr-1, Bcl-2 and Mcl-1 protein expression were observed in HL-60/VCR cells. In both HL-60 and HL-60/VCR cells, 14-3-3ζ was observed in the cytoplasm and nuclear compartments. 14-3-3ζ siRNA significantly reduced HL-60 and HL-60/VCR cell growth after 48 h and increased the proportion of cells in the G0/G1 phase. Moreover, 14-3-3ζ siRNA significantly increased the sensitivity of both HL-60 and HL-60/VCR cells to TPT, possibly through the inhibition of Bcl-2, Mcl-1 and mdr-1 protein expression.
Conclusions:
Silencing of 14-3-3ζ increased the sensitivity of both sensitive and resistant HL-60 cells to TPT-induced apoptosis, possibly through altering the expression of apoptosis-associated proteins, suggesting that it may be a potential target for MDR AML.
© 2014 S. Karger AG, Basel.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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14-3-3 Proteins / antagonists & inhibitors
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14-3-3 Proteins / biosynthesis
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14-3-3 Proteins / genetics
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14-3-3 Proteins / physiology*
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
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Antineoplastic Agents, Phytogenic / pharmacology
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Apoptosis / drug effects
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Apoptosis / genetics
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Apoptosis / physiology
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Cell Cycle / drug effects
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Cell Cycle / genetics
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Drug Resistance, Multiple / genetics*
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Drug Resistance, Neoplasm / genetics*
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Gene Expression Profiling
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Gene Expression Regulation, Leukemic*
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HL-60 Cells / drug effects
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HL-60 Cells / enzymology*
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Humans
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Myeloid Cell Leukemia Sequence 1 Protein / biosynthesis
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Myeloid Cell Leukemia Sequence 1 Protein / genetics
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Oligonucleotide Array Sequence Analysis
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis
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Proto-Oncogene Proteins c-bcl-2 / genetics
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RNA Interference
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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RNA, Neoplasm / biosynthesis
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RNA, Neoplasm / genetics
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RNA, Small Interfering / pharmacology
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Subcellular Fractions / metabolism
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Topoisomerase I Inhibitors / pharmacology
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Topotecan / pharmacology
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Vincristine / pharmacology
Substances
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14-3-3 Proteins
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ABCB1 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Antineoplastic Agents, Phytogenic
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MCL1 protein, human
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins
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Proto-Oncogene Proteins c-bcl-2
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RNA, Messenger
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RNA, Neoplasm
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RNA, Small Interfering
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Topoisomerase I Inhibitors
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YWHAZ protein, human
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Vincristine
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Topotecan