title: Role of hERG1 K(+) channels in leukemia cells as a positive regulator in SDF-1a-induced proliferation.
abstract: Previous work from our laboratory has confirmed that human ether-à-go-go-related gene 1 (hERG1) K(+) channels are constitutively expressed in leukemia cells and enhanced cell proliferation. More importantly, it has shown that stromal cell-derived factor-1a (SDF-1a) significantly increases hERG1 K(+) tail current and a specific hERG1 K(+) channels inhibitor significantly blocks SDF-1a-induced migration of leukemic cells. In this study, we investigated a possible regulatory effect of hERG1 K(+) channels upon SDF-1a-mediated cell proliferation as a mean to uncover new molecular events involved in bone marrow microenvironment and leukemogenesis. RT-PCR showed that SDF-1a enhanced hERG1 expression in a dose-dependent manner. Cell proliferation assay illustrated that SDF-1a promoted cell proliferation in a dose-dependent manner, whereas this effect was impaired by E-4031. In addition, E-4031 inhibited SDF-1a-stimulated leukemic cell proliferation by inducing G(0)/G(1) arrest. Interestingly, E-4031 promoted SDF-1a-induced apoptosis in HL-60 and leukemic blasts, which markedly impaired the protection effect of SDF-1a in AML. Moreover, SDF-1a increased the expression of Wnt/beta-catenin target genes, including beta-catenin, cyclin-D1, and c-myc; however, this manner was abolished by blockage with the hERG1 K(+) channels. Taken together, our results provide evidence of a novel mechanism involved in the proliferative effects of SDF-1a and highlight hERG1 K(+) channels as a therapeutic target for leukemia treatment and prevention.
authors.affiliation: Center for Stem Cell Research and Application, Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Zheng
authors.forename: Huiyu
authors.initials: H
authors.lastname: Li
authors.forename: Wen
authors.initials: W
authors.lastname: Du
authors.forename: Shiang
authors.initials: S
authors.lastname: Huang
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects*; D054377:Chemokine CXCL12 / Q000494:pharmacology*; D019938:Cyclin D1 / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics* / Q000502:physiology; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010880:Piperidines / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D016192:Resting Phase, Cell Cycle / Q000187:drug effects / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051176:beta Catenin / Q000235:genetics
chemical_list: D054377:Chemokine CXCL12; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; C489427:MYC protein, human; D010880:Piperidines; D016271:Proto-Oncogene Proteins c-myc; D011725:Pyridines; D051176:beta Catenin; C063968:E 4031; D019938:Cyclin D1