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Open Access Highly Accessed Research article

Docosahexaenoic acid-induced apoptosis is mediated by activation of mitogen-activated protein kinases in human cancer cells

Soyeon Jeong13, Kaipeng Jing13, Nayeong Kim13, Soyeon Shin13, Soyeon Kim13, Kyoung-Sub Song1, Jun-Young Heo1, Ji-Hoon Park1, Kang-Sik Seo1, Jeongsu Han1, Tong Wu4, Gi-Ryang Kweon1, Seung-Kiel Park1, Jong-Il Park1 and Kyu Lim123*

Author Affiliations

1 Department of Biochemistry, School of Medicine, Chungnam National University, Daejeon 301-747, Korea

2 Cancer Research Institute, School of Medicine, Chungnam National University, Daejeon 301-747, Korea

3 Infection Signaling Network Research Center, School of Medicine, Chungnam National University, Daejeon 301-747, Korea

4 Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA

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BMC Cancer 2014, 14:481  doi:10.1186/1471-2407-14-481

Published: 3 July 2014

Abstract

Background

The role of omega-3 polyunsaturated fatty acids (ω3-PUFAs) in cancer prevention has been demonstrated; however, the exact molecular mechanisms underlying the anticancer activity of ω3-PUFAs are not fully understood. Here, we investigated the relationship between the anticancer action of a specific ω3-PUFA docosahexaenoic acid (DHA), and the conventional mitogen-activated protein kinases (MAPKs) including extracellular signal-regulated kinase (ERK), c-JUN N-terminal kinase (JNK) and p38 whose dysregulation has been implicated in human cancers.

Methods

MTT assays were carried out to determine cell viability of cancer cell lines (PA-1, H1299, D54MG and SiHa) from different origins. Apoptosis was confirmed by TUNEL staining, DNA fragmentation analysis and caspase activity assays. Activities of the conventional MAPKs were monitored by their phosphorylation levels using immunoblotting and immunocytochemistry analysis. Reactive oxygen species (ROS) production was measured by flow cytometry and microscopy using fluorescent probes for general ROS and mitochondrial superoxide.

Results

DHA treatment decreased cell viability and induced apoptotic cell death in all four studied cell lines. DHA-induced apoptosis was coupled to the activation of the conventional MAPKs, and knockdown of ERK/JNK/p38 by small interfering RNAs reduced the apoptosis induced by DHA, indicating that the pro-apoptotic effect of DHA is mediated by MAPKs activation. Further study revealed that the DHA-induced MAPKs activation and apoptosis was associated with mitochondrial ROS overproduction and malfunction, and that ROS inhibition remarkably reversed these effects of DHA.

Conclusion

Together, these results indicate that DHA-induced MAPKs activation is dependent on its capacity to provoke mitochondrial ROS generation, and accounts for its cytotoxic effect in human cancer cells.

Keywords:
Docosahexaenoic acid; Reactive oxygen species; Mitogen-activated protein kinases; Apoptosis; Cancer