Bmal1 suppresses cancer cell invasion by blocking the phosphoinositide 3-kinase-Akt-MMP-2 signaling pathway

Jung,Chan-Hun; Kim,Eun  Mi; Park,Jong  Kuk; Hwang,Sang-Gu; Moon,Sung-Kwon; Kim,Wun-Jae; Um,Hong-Duck

doi:10.3892/or.2013.2381

Bmal1 suppresses cancer cell invasion by blocking the phosphoinositide 3-kinase-Akt-MMP-2 signaling pathway

Authors:
- Chan-Hun Jung
- Eun Mi Kim
- Jong Kuk Park
- Sang-Gu Hwang
- Sung-Kwon Moon
- Wun-Jae Kim
- Hong-Duck Um
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Affiliations: Division of Radiation Cancer Biology, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea, Department of Biotechnology, Chungju National University, Chungju, Chungbuk, Republic of Korea, Department of Urology, College of Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
Published online on: April 3, 2013 https://doi.org/10.3892/or.2013.2381
Pages: 2109-2113
Copyright: © Jung et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Bmal1 is a core factor in the regulation of circadian rhythms. Previous studies have shown that Bmal1 suppresses tumor growth in cell culture and animal models and is downregulated in certain types of cancer. The aim of the present study was to investigated whether Bmal1 influences the invasiveness of cancer cells. We demonstrated that knockdown of Bmal1 by RNA interference promoted cancer cell invasion, whereas its overexpression reduced cellular invasiveness. These effects were observed in lung cancer and glioma cells, and occurred regardless of p53 status. Therefore, it appears that Bmal1 suppresses the invasion of multiple cancer types in a p53-independent manner. Bmal1 knockdown-induced cancer cell invasion was accompanied by activation of the PI3K-Akt-MMP-2 pathway, and was prevented by inhibitors of PI3K, Akt or MMP-2. This suggests that Bmal1 suppresses cell invasion by blocking the PI3K-Akt-MMP-2 pathway. Since this invasion pathway is activated by the oncogene Bcl-w, we investigated whether Bmal1 affects the activity of Bcl-w. As expected, Bmal1 attenuated the ability of Bcl-w to promote MMP-2 accumulation and cell invasion, supporting the idea that Bmal1 antagonizes Bcl-w activity. Collectively, our data suggest that Bmal1 is a tumor suppressor, capable of suppressing cancer cell growth and invasiveness, and support the recent proposal that there is a tight molecular link between circadian rhythms and tumor formation/progression.

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