title: Glucose-6-phosphate dehydrogenase and NADPH oxidase 4 control STAT3 activity in melanoma cells through a pathway involving reactive oxygen species, c-SRC and SHP2.
abstract: BACKGROUND
  Glucose-6-phosphate dehydrogenase (G6PD) participates in glucose utilization by catalysing the first step of the pentose-phosphate pathway in mammalian cells. Previous studies have shown that changes in G6PD levels can promote tumor cell proliferation or apoptosis via the STAT3/5 pathway in a human melanoma xenograft model. G6PD cooperates with NADPH oxidase 4 (NOX4) in the cellular metabolism of reactive oxygen species (ROS) and in maintaining the intracellular redox state.
  
  
  METHODS
  In this study, the effect of G6PD or NOX4 silencing in the melanoma line A375 was examined in terms of redox state, proto-oncogene tyrosine-protein kinase Src (c-Src) and the tyrosine-specific protein phosphatase SHP2 expression as well as cell cycle progression.
  
  
  RESULTS
  The results demonstrate that: (1) Downregulation of cyclin D1 and CDK4 and up-regulation of p53 and p21 occurred in response to silencing of G6PD and NOX4 thus resulting in G1/S cell cycle arrest and inhibition of A375 cell proliferation. (2) The blockade of cell proliferation is primarily due to a reduced DNA-binding activity of STAT3. (3) The DNA-binding activity of STAT3 was regulated by the upstream factors, c-SRC and SHP2. Silencing of NOX4 in A375 cells inhibited c-SRC and SHP2 regulated STAT3 activity.
  
  
  CONCLUSIONS
  The data are consistent with a novel G6PD-NOX4-NADPH-ROS-c-SRC/SHP2 pathway controlling STAT3 activity in A375 melanoma cells.
authors.affiliation: Department of Biochemistry and Molecular Biology, Kunming Medical University Kunming 650500, China.
authors.forename: Tianchi
authors.initials: T
authors.lastname: Cai
authors.affiliation: The First Hospital affiliated to Kunming Medical University Kunming 650032, China.
authors.forename: Yingmin
authors.initials: Y
authors.lastname: Kuang
authors.affiliation: Department of Biochemistry and Molecular Biology, Kunming Medical University Kunming 650500, China ; The Maternal and Child Health Hospital of Yunnan Province Kunming 650051, China.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Kunming Medical University Kunming 650500, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Kunming Medical University Kunming 650500, China.
authors.forename: Long
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, Kunming Medical University Kunming 650500, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, Kunming Medical University Kunming 650500, China.
authors.forename: Yuqian
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, Kunming Medical University Kunming 650500, China.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Kunming Medical University Kunming 650500, China.
authors.forename: Huixin
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Molecular Biology, Kunming Medical University Kunming 650500, China.
authors.forename: Qiaoqiao
authors.initials: Q
authors.lastname: Han
authors.affiliation: Department of Biochemistry and Molecular Biology, Kunming Medical University Kunming 650500, China.
authors.forename: Yuechun
authors.initials: Y
authors.lastname: Zhu
keywords: CDK4; Glucose-6-phosphate dehydrogenase; NOX4; SHP2; STAT3/5; c-SRC; cyclin D1