title: Paradoxical induction of growth arrest and apoptosis by EGF via the up-regulation of PTEN by activating Redox factor-1/Egr-1 in human lung cancer cells.
abstract: Epidermal growth factor (EGF) signaling promotes cell proliferation and survival in several types of cancer. Here, however, we showed that EGF inhibits proliferation and promotes programmed cell death in non-small cell lung cancer (NSCLC) cells. In A549 cells, EGF increased redox factor-1 (Ref-1) expression and the association of Ref-1 with zinc finger-containing transcriptional regulator (EGR1) via activation of p22phox, RAC1, and an NADPH oxidase subunit. EGF increased p22phox and RAC1 expression through activation of purinergic receptors (P2Y). Elevated Ref-1/EGR1 levels increased phosphatase and tensin homolog (PTEN) levels, leading to inhibition of the Akt pathway. EGF-induced PTEN upregulation increased apoptosis and autophagy-induced damage in A549 cells, whereas Ref-1 knockdown blocked EGF-induced PTEN upregulation in an NADPH oxidase p22phox subunit-independent manner. In addition, p22phox knockdown restored EGF-induced effects, implying that changes in P2Y activity caused by EGF, which activates NADPH oxidase via RAC1, influenced Ref-1-mediated redox regulation. Finally, EGF similarly attenuated cell proliferation and promoted autophagy and apoptosis in vivo in a xenograft model using A549 cells. These findings reveal that EGF-induced redox signaling is linked to Ref-1-induced death in NSCLC cells.
authors.affiliation: Department of Radiation Oncology, Asan Medical Center and University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Je-Won
authors.initials: JW
authors.lastname: Ryu
authors.affiliation: Department of Biological Sciences, Institute of Molecular Biology and Genetics, National Creative Research Institutive Center for Adipose Tissue Remodeling, Seoul National University, Seoul, Republic of Korea.
authors.forename: Sung Sik
authors.initials: SS
authors.lastname: Choe
authors.affiliation: Department of Radiation Oncology, Asan Medical Center and University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Seung-Hee
authors.initials: SH
authors.lastname: Ryu
authors.affiliation: Department of Radiation Oncology, Asan Medical Center and University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Park
authors.affiliation: Asan Institute for Life Science, Asan Medical Center and University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Byoung Wook
authors.initials: BW
authors.lastname: Lee
authors.affiliation: Department of Life Science, College of Natural Science, Hallym University, Kyeongki Province, Republic of Korea.
authors.forename: Tae Keun
authors.initials: TK
authors.lastname: Kim
authors.affiliation: Asan Institute for Life Science, Asan Medical Center and University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Chang Hoon
authors.initials: CH
authors.lastname: Ha
authors.affiliation: Department of Radiation Oncology, Asan Medical Center and University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Sang-Wook
authors.initials: SW
authors.lastname: Lee
mesh_terms: D000072283:A549 Cells; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics / Q000378:metabolism*; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000008:administration & dosage* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D004815:Epidermal Growth Factor; D019255:NADPH Oxidases; C086986:CYBA protein, human; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase
keywords: epidermal growth factor (EGF); phosphatase and tensin homolog (PTEN); purinergic receptor 2(P2Y); redox factor-1(Ref-1); zinc finger-containing transcriptional regulator 1(EGR1)