Volume 51, Issue 1 p. 87-93

Sphingosine kinase 1 pathway is involved in melatonin-induced HIF-1α inactivation in hypoxic PC-3 prostate cancer cells

Sung-Yun Cho

Sung-Yun Cho

College of Oriental Medicine, Kyung Hee University, Seoul, South Korea

These authors contributed equally to this study.

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Hyo-Jeong Lee

Hyo-Jeong Lee

College of Oriental Medicine, Kyung Hee University, Seoul, South Korea

These authors contributed equally to this study.

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Soo-Jin Jeong

Soo-Jin Jeong

College of Oriental Medicine, Kyung Hee University, Seoul, South Korea

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Hyo-Jung Lee

Hyo-Jung Lee

College of Oriental Medicine, Kyung Hee University, Seoul, South Korea

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Hyun-Seok Kim

Hyun-Seok Kim

Yonsei University School of Medicine, Seoul, South Korea

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Chang Yan Chen

Chang Yan Chen

Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

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Eun-Ok Lee

Eun-Ok Lee

College of Oriental Medicine, Kyung Hee University, Seoul, South Korea

These authors contributed equally to this study.

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Sung-Hoon Kim

Sung-Hoon Kim

College of Oriental Medicine, Kyung Hee University, Seoul, South Korea

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First published: 01 February 2011
Citations: 71
Address reprint requests to Sung-Hoon Kim, Cancer Preventive Material Development Research Center, College of Oriental Medicine, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, South Korea.
E-mail: [email protected]

Abstract

Abstract: Sphingosine kinase 1 (SPHK1) is a newly discovered modulator of hypoxia inducible factor 1α (HIF-1α) with various biological activities such as cell growth, survival, invasion, angiogenesis, and carcinogenesis. Thus, in the present study, the biological mechanisms of melatonin were elucidated in association with SPHK1 pathway in PC-3 prostate cancer cells under hypoxia. Melatonin inhibited the stability of HIF-1α in a time- and concentration- dependent manners. Also, melatonin decreased SPHK1 activity in PC-3 cells during hypoxia. Furthermore, melatonin suppressed AKT/glycogen synthase kinase-3β (GSK-3β) signaling pathway, which stabilizes HIF-1α via inhibition of von Hippel-Lindau tumor suppressor protein. Consistently, siRNA-SPHK1 and sphingosine kinase inhibitor (SKI) effectively blocked the expression of HIF-1α, phospho-AKT and vascular endothelial growth factor (VEGF) production in PC-3 cells under hypoxia, suggesting the role of SPHK1 in melatonin-inhibited HIF-1α accumulation. Moreover, reactive oxygen species (ROS) scavenger N-acteylcysteine enhanced melatonin-inhibited HIF-1α expression and SPHK1 activity. Overall, our findings suggest that melatonin suppresses HIF-1α accumulation via inhibition of SPHK1 pathway and ROS generation in PC-3 cells under hypoxia.

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