Research Papers:

sMEK1 inhibits endothelial cell proliferation by attenuating VEGFR-2-dependent-Akt/eNOS/HIF-1α signaling pathways

Boh-Ram Kim, Seung Hee Seo, Mi Sun Park, Seung-Hoon Lee, Youngjoo Kwon and Seung Bae Rho _

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Oncotarget. 2015; 6:31830-31843. https://doi.org/10.18632/oncotarget.5570

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Boh-Ram Kim1,3,*, Seung Hee Seo1,*, Mi Sun Park1, Seung-Hoon Lee2, Youngjoo Kwon3 and Seung Bae Rho1

1 Research Institute, National Cancer Center, Ilsan-ro, Ilsandong-gu, Goyang-si Gyeonggi-do, Republic of Korea

2 Department of Life Science, Yong In University, Samga-dong, Cheoin-gu, Yongin-si Gyeonggi-do, Republic of Korea

3 College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Global Top 5 Program, Ewha Womans University, Seoul, Republic of Korea

* This authors have contributed equally to this work

Correspondence to:

Seung Bae Rho, email:

Keywords: sMEK1 tumor suppressor; hypoxic condition; anti-angiogenic activity; ovarian tumor; xenograft model

Received: June 28, 2015 Accepted: August 15, 2015 Published: September 10, 2015


The suppressor of MEK null (sMEK1) protein possesses pro-apoptotic activities. In the current study, we reveal that sMEK1 functions as a novel anti-angiogenic factor by suppressing vascular endothelial growth factor (VEGF)-induced cell proliferation, migration, and capillary-like tubular structure in vitro. In addition, sMEK1 inhibited the phosphorylation of the signaling components up- and downstream of Akt, including phospholipase Cγ1 (PLC-γ1), 3-phosphoinositide-dependent protein kinase 1 (PDK1), endothelial nitric oxide synthetase (eNOS), and hypoxia-inducible factor 1 (HIF-1α) during ovarian tumor progression via binding with vascular endothelial growth factor receptor 2 (VEGFR-2). Furthermore, sMEK1 decreased tumor vascularity and inhibited tumor growth in a xenograft human ovarian tumor model. These results supply convincing evidence that sMEK1 controls endothelial cell function and subsequent angiogenesis by suppressing VEGFR-2-mediated PI3K/Akt/eNOS signaling pathway. Taken together, our results clearly suggest that sMEK1 might be a novel anti-angiogenic and anti-tumor agent for use in ovarian tumor.

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