Abstract
A small population of cancer stem cells named the "side population" (SP) has been demonstrated to be responsible for the persistence of many solid tumors. However, the role of the SP in leukemic pathogenesis remains controversial. The resistance of leukemic stem cells to targeted therapies, such as tyrosine kinase inhibitors (TKIs), results in therapeutic failure or refractory/relapsed disease in chronic myeloid leukemia (CML). The drug pump, ATP-binding cassette sub-family G member 2 (ABCG2), is well known as a specific marker of the SP and could be controlled by several pathways, including the PI3K/Akt pathway. Our data demonstrated that compared with wild-type K562 cells, the higher percentage of ABCG2+ cells corresponded to the higher SP fraction in K562/ABCG2 (ABCG2 overexpressing) and K562/IMR (resistance to imatinib) cells, which exhibited enhanced drug resistance along with downregulated phosphatase and tensin homologue deleted on chromosome -10 (PTEN) and activated phosphorylated-Akt (p-Akt). PTEN and p-Akt downregulation could be abrogated by both the PI3K inhibitor LY294002 and the mTOR inhibitor rapamycin. Moreover, in CML patients in the accelerated phase/blastic phase (AP/BP), increased SP phenotype rather than ABCG2 expression was accompanied by the loss of PTEN protein and the up-regulation of p-Akt expression. These results suggested that the expression of ABCG2 and the SP may be regulated by PTEN through the PI3K/Akt pathway, which would be a potentially effective strategy for targeting CML stem cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters / genetics
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ATP-Binding Cassette Transporters / metabolism*
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Adult
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Aged
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Apoptosis / drug effects
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Blotting, Western
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Cell Survival / drug effects
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Chromones / pharmacology
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Enzyme Inhibitors / pharmacology
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Female
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Humans
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K562 Cells
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
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Male
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Middle Aged
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Mitoxantrone / pharmacology
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Morpholines / pharmacology
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology
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PTEN Phosphohydrolase / genetics
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PTEN Phosphohydrolase / metabolism*
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins c-akt / metabolism*
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Side-Population Cells / metabolism*
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Signal Transduction / drug effects
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Sirolimus / pharmacology
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Young Adult
Substances
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ABCG2 protein, human
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters
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Chromones
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Enzyme Inhibitors
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Morpholines
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Neoplasm Proteins
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Phosphoinositide-3 Kinase Inhibitors
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Mitoxantrone
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Proto-Oncogene Proteins c-akt
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PTEN Phosphohydrolase
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PTEN protein, human
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Sirolimus
Grants and funding
This work was supported by the National Natural Science Foundation of China (Grant No. 81100328), the Doctoral Fund of Ministry of Education of China (Grant No. 20110162120010), and the Fundamental Research Funds for the Central Universities (Grant No. 2011QNZT151) to HZ and the National Natural Science Foundation of China (Grant No. 81170477) to F-PC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.