title: TrkC promotes survival and growth of leukemia cells through Akt-mTOR-dependent up-regulation of PLK-1 and Twist-1.
abstract: It has been suggested that activation of receptor PTKs is important for leukemogenesis and leukemia cell response to targeted therapy in hematological malignancies including leukemia. PTKs induce activation of the PI3K/Akt/mTOR pathway, which can result in prevention of apoptosis. Here, we describe an important role of the TrkC-associated molecular network in the process of leukemogenesis. TrkC was found to be frequently overexpressed in human leukemia cells and leukemia subtypes. In U937 human leukemia cells, blockade of TrkC using small hairpin RNA (shRNA) specific to TrkC or K562a, a specific inhibitor of TrkC, resulted in a significant decrease in growth and survival of the cells, which was closely associated with reduced mTOR level and Akt activity. In addition, TrkC enhances the survival and proliferation of leukemia, which is correlated with activation of the PI3K/Akt pathway. Moreover, TrkC significantly inhibits apoptosis via induction of the expression of PLK-1 and Twist-1 through activation of AKT/mTor pathway; therefore, it plays a key role in leukemogenesis. These findings reveal an unexpected physiological role for TrkC in the pathogenesis of leukemia and have important implications for understanding various hematological malignancies.
authors.affiliation: Department of Molecular Medicine, School of Medicine, Gachon University, Incheon 406-840, Korea.
authors.forename: Min Soo
authors.initials: MS
authors.lastname: Kim
authors.forename: Gyoung Mi
authors.initials: GM
authors.lastname: Kim
authors.forename: Yun-Jeong
authors.initials: YJ
authors.lastname: Choi
authors.forename: Hye Joung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Yoo-Jin
authors.initials: YJ
authors.lastname: Kim
authors.forename: Wook
authors.initials: W
authors.lastname: Jin
mesh_terms: D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D015973:Gene Expression Regulation, Leukemic; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D020812:Receptor, trkC / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism; D020298:U937 Cells; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D020812:Receptor, trkC; D058570:TOR Serine-Threonine Kinases; D051879:Twist-Related Protein 1; D000097869:Polo-Like Kinase 1; C103173:TWIST1 protein, human; C546842:MTOR protein, human