title: PTEN regulates BCRP/ABCG2 and the side population through the PI3K/Akt pathway in chronic myeloid leukemia.
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.
authors.affiliation: Department of Hematology, Xiang Ya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Fang-Fang
authors.initials: FF
authors.lastname: Huang
authors.affiliation: Department of Hematology, West China Hospital, Si Chuan University, Chengdu, Sichuan, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Hematology, Xiang Ya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Deng-Shu
authors.initials: DS
authors.lastname: Wu
authors.affiliation: Department of Hematology, Xiang Ya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Yuan
authors.affiliation: Department of Hematology, Xiang Ya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Yan-Hui
authors.initials: YH
authors.lastname: Yu
authors.affiliation: Department of Hematology, Xiang Ya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Xie-Lan
authors.initials: XL
authors.lastname: Zhao
authors.affiliation: Department of Hematology, Xiang Ya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Fang-Ping
authors.initials: FP
authors.lastname: Chen
authors.affiliation: Department of Hematology, Xiang Ya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zeng
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058985:Side-Population Cells / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D002867:Chromones; D004791:Enzyme Inhibitors; D008942:Mitoxantrone; D009025:Morpholines; D009363:Neoplasm Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; C116614:ABCG2 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494929:PTEN protein, human