title: Inhibition of BMK1 pathway suppresses cancer stem cells through BNIP3 and BNIP3L.
abstract: Cancer stem cells (CSCs) possess many characteristics associated with stem cells and are believed to drive tumor initiation. Although targeting of CSCs offers great promise for the new generation of therapeutics, lack of the effective drugable target and appropriate pharmacological reagents significantly impedes the development of chemotherapies. Here, we show that the phosphorylation of BMK1 was significantly correlated with not only embryonic and induced pluripotent stem (iPS) cells, but also the CSCs. It was showed that activation of BMK1 by the expression of MEK5D enhanced the self-renew (sphere formation), proliferation (clone formation) and tumorigenic capacity of CSCs. While BMK1 inhibitor, XMD8-92, suppressed these capacities. RNA-seq and microarray analysis revealed that inhibition of BMK1 significantly enhanced the expression of BNIP3 and BNIP3L, which play important roles in cell death. Further study indicated that shRNA-mediated knock down of BNIP3 and BNIP3L impairs the BMK1 inhibitor, XMD8-92-induced suppression of sphere formation and clone formation of CSC. Collectively, these results not only indicate that BMK1 plays an important role in maintaining "stemness" of CSCs, but also implicate that BMK1 might be a potential drug target for CSCs.
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of DaLian Medical University, Institute of Cancer Stem Cell, DaLian Medical University, Dalian, Liaoning 116044, China.
authors.forename: Chengli
authors.initials: C
authors.lastname: Song
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of DaLian Medical University, Institute of Cancer Stem Cell, DaLian Medical University, Dalian, Liaoning 116044, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of DaLian Medical University, Institute of Cancer Stem Cell, DaLian Medical University, Dalian, Liaoning 116044, China.
authors.forename: Kui
authors.initials: K
authors.lastname: Jiang
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of DaLian Medical University, Institute of Cancer Stem Cell, DaLian Medical University, Dalian, Liaoning 116044, China.
authors.forename: Guangyu
authors.initials: G
authors.lastname: Zhou
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of DaLian Medical University, Institute of Cancer Stem Cell, DaLian Medical University, Dalian, Liaoning 116044, China.
authors.forename: Xuebin
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of DaLian Medical University, Institute of Cancer Stem Cell, DaLian Medical University, Dalian, Liaoning 116044, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of DaLian Medical University, Institute of Cancer Stem Cell, DaLian Medical University, Dalian, Liaoning 116044, China.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of DaLian Medical University, Institute of Cancer Stem Cell, DaLian Medical University, Dalian, Liaoning 116044, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Fang
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of DaLian Medical University, Institute of Cancer Stem Cell, DaLian Medical University, Dalian, Liaoning 116044, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Jiing-Dwan
authors.initials: JD
authors.lastname: Lee
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors.forename: Shi-Cang
authors.initials: SC
authors.lastname: Yu
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of DaLian Medical University, Institute of Cancer Stem Cell, DaLian Medical University, Dalian, Liaoning 116044, China.
authors.forename: Qingkai
authors.initials: Q
authors.lastname: Yang
mesh_terms: D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D024101:Mitochondrial Proteins / Q000502:physiology*; D048054:Mitogen-Activated Protein Kinase 7 / Q000037:antagonists & inhibitors* / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C508686:BNip3 protein, mouse; D001570:Benzodiazepinones; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C501741:Nix protein, mouse; D034741:RNA, Small Interfering; C568790:XMD 8-92; D048054:Mitogen-Activated Protein Kinase 7
keywords: BMK1; cancer stem cell; kinase