Research Papers:

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

Je-won Ryu, Sung Sik Choe, Seung-Hee Ryu, Eun-Young Park, Byoung Wook Lee, Tae Keun Kim, Chang Hoon Ha and Sang-wook Lee _

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Oncotarget. 2017; 8:4181-4195. https://doi.org/10.18632/oncotarget.13809

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Je-won Ryu1,*, Sung Sik Choe2,*, Seung-Hee Ryu1, Eun-Young Park1, Byoung Wook Lee3, Tae Keun Kim4, Chang Hoon Ha3, Sang-wook Lee1

1Department of Radiation Oncology, Asan Medical Center and University of Ulsan College of Medicine, Seoul, Republic of Korea

2Department 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

3Asan Institute for Life Science, Asan Medical Center and University of Ulsan College of Medicine, Seoul, Republic of Korea

4Department of Life Science, College of Natural Science, Hallym University, Kyeongki Province, Republic of Korea

*These authors contributed equally to this work

Correspondence to:

Chang Hoon Ha, email: [email protected]

Sang-Wook Lee, email: [email protected]

Keywords: Epidermal Growth Factor (EGF), Purinergic Receptor 2(P2Y), Redox Factor-1(Ref-1), Zinc Finger-containing Transcriptional Regulator 1(EGR1), Phosphatase and Tensin Homolog (PTEN)

Received: September 30, 2016     Accepted: November 24, 2016     Published: December 07, 2016


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.

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