title: IGFBP7 induces apoptosis of acute myeloid leukemia cells and synergizes with chemotherapy in suppression of leukemia cell survival.
abstract: Despite high remission rates after chemotherapy, only 30-40% of acute myeloid leukemia (AML) patients survive 5 years after diagnosis. This extremely poor prognosis of AML is mainly caused by treatment failure due to chemotherapy resistance. Chemotherapy resistance can be caused by various features including activation of alternative signaling pathways, evasion of cell death or activation of receptor tyrosine kinases such as the insulin growth factor-1 receptor (IGF-1R). Here we have studied the role of the insulin-like growth factor-binding protein-7 (IGFBP7), a tumor suppressor and part of the IGF-1R axis, in AML. We report that IGFBP7 sensitizes AML cells to chemotherapy-induced cell death. Moreover, overexpression of IGFBP7 as well as addition of recombinant human IGFBP7 is able to reduce the survival of AML cells by the induction of a G2 cell cycle arrest and apoptosis. This effect is mainly independent from IGF-1R activation, activated Akt and activated Erk. Importantly, AML patients with high IGFBP7 expression have a better outcome than patients with low IGFBP7 expression, indicating a positive role for IGFBP7 in treatment and outcome of AML. Together, this suggests that the combination of IGFBP7 and chemotherapy might potentially overcome conventional AML drug resistance and thus might improve AML patient survival.
authors: Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands.
authors: H Jmp
authors: HJ
authors: Verhagen
authors: Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands.
authors: D C
authors: DC
authors: de Leeuw
authors: Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands.
authors: M Gm
authors: MG
authors: Roemer
authors: Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands.
authors: F
authors: F
authors: Denkers
authors: Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands.
authors: W
authors: W
authors: Pouwels
authors: Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands.
authors: A
authors: A
authors: Rutten
authors: Protein Facility, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: P H
authors: PH
authors: Celie
authors: Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands.
authors: G J
authors: GJ
authors: Ossenkoppele
authors: Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands.
authors: G J
authors: GJ
authors: Schuurhuis
authors: Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands.
authors: L
authors: L
authors: Smit
mesh_terms: D017209:Apoptosis; D002470:Cell Survival; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D018922:HL-60 Cells; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D018969:Insulin-Like Growth Factor Binding Proteins; D025521:Tumor Suppressor Proteins; C102529:insulin-like growth factor binding protein-related protein 1; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases