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Piperine inhibits IL-1β-induced IL-6 expression by suppressing p38 MAPK and STAT3 activation in gastric cancer cells

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Abstract

Piperine, a kind of natural alkaloid found in peppers, has been reported to exhibit anti-oxidative and anti-tumor activities, both in vitro and in vivo. Interleukin-6 (IL-6) is an important cytokine that activates the signal transduction, promotes tumor cell metastasis, and induces malignancy, including in gastric cancer. However, the effects of piperine on IL-6 expression in gastric cancer cells have not yet been well defined. In this study, we investigated the effects of piperine on the IL-6 expression, and examined the underlying signaling pathways via RT-PCR, promoter studies and Western blotting in human gastric cancer TMK-1 cells. Our results showed that piperine inhibited interleukin-1β (IL-1β)–induced IL-6 expression in a dose-dependent manner. In addition, piperine also inhibited IL-6 promoter activity. Experiments with mitogen-activated protein kinase (MAPK) inhibitors and dominant negative mutant p38 MAPK indicated that p38 MAPK was essential for IL-6 expression in the TMK-1 cells. Additionally, signal transducer and activator of transcription 3 (STAT3) was also involved in the IL-1β-induced IL-6 expression in gastric cancer cells. Piperine inhibited IL-1β-induced p38 MAPK and STAT3 activation and, in turn, blocked the IL-1β-induced IL-6 expression. Furthermore, gastric cancer cells pretreated with IL-1β showed markedly enhanced invasiveness, which was partially abrogated by treatment with IL-6 siRNA, piperine, and inhibitors of p38 MAPK and STAT3. These results suggest that piperine may exert at least part of its anti-cancer effect by controlling IL-6 expression through the suppression of p38 MAPK and STAT3.

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Acknowledgments

We are very grateful to Dr. DY Yoon (Konkuk University, Korea) for the IL-6-promoter reporter construct. This study was supported by a research grant (0720570) from the National Cancer Center, by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education, Science, and Technology (2010-0009910), and by a Medical Research Center (2012-000-9442) grant from the Korean Science and Engineering Foundation.

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  1. Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, 501-190, Republic of Korea

    Yong Xia, Pham Ngoc Khoi, Hyun Joong Yoon, Sen Lian, Young Eun Joo, Kee Oh Chay, Kyung Keun Kim & Young Do Jung

  2. Department of Biochemistry, Chonnam National University Medical School, 5 Hakdong, Gwangju, 501-190, Republic of Korea

    Young Do Jung

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  1. Yong Xia
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Xia, Y., Khoi, P.N., Yoon, H.J. et al. Piperine inhibits IL-1β-induced IL-6 expression by suppressing p38 MAPK and STAT3 activation in gastric cancer cells. Mol Cell Biochem 398, 147–156 (2015). https://doi.org/10.1007/s11010-014-2214-0

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