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Apigenin induces apoptosis via extrinsic pathway, inducing p53 and inhibiting STAT3 and NFκB signaling in HER2-overexpressing breast cancer cells

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An Erratum to this article was published on 15 June 2012

Abstract

Phytoestrogens are known to prevent tumor induction. But their molecular mechanisms of action are still unknown. This study aimed to examine the effect of apigenin on proliferation and apoptosis in HER2-expressing breast cancer cells. In our experiments, apigenin inhibited the proliferation of MCF-7 vec and MCF-7 HER2 cells. This growth inhibition was accompanied with an increase of sub G0/G1 apoptotic fractions. Overexpression of HER2 did not confer resistance to apigenin in MCF-7 cells. Apigenin-induced extrinsic apoptosis pathway up-regulating the levels of cleaved caspase-8, and inducing the cleavage of poly (ADP-ribose) polymerase, whereas apigenin did not induce apoptosis via intrinsic mitochondrial apoptosis pathway since this compound did not decrease mitochondrial membrane potential maintaining red fluorescence and did not affect the levels of B-cell lymphoma 2 (BCL2) and Bcl-2-associated X protein. Moreover, apigenin reduced the tyrosine phosphorylation of HER2 (phospho-HER2 level) in MCF-7 HER2 cells, and up-regulated the levels of p53, phospho-p53 and p21 in MCF-7 vec and MCF-7 HER2 cells. This suggests that apigenin induces apoptosis through p53-dependent pathway. Apigenin also reduced the expression of phospho-JAK1 and phospho-STAT3 and decreased STAT3-dependent luciferase reporter gene activity in MCF-7 vec and MCF-7 HER2 cells. Apigenin decreased the phosphorylation level of IκBα in the cytosol, and abrogated the nuclear translocation of p65 within the nucleus suggesting that it blocks the activation of NFκB signaling pathway in MCF-7 vec and MCF-7 HER2 cells. Our study indicates that apigenin could be a potential useful compound to prevent or treat HER2-overexpressing breast cancer.

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Acknowledgments

This study was supported by a Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (MEST) (No. 2009-0063466). This study was also supported by a grant of the Traditional Korean Medicine R&D Project, Ministry of Health & Welfare, Republic of Korea (B110043).

Conflict of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

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Authors and Affiliations

  1. Laboratory of Clinical Biology and Pharmacogenomics and Center for Clinical Research and Genomics, Institute of Oriental Medicine, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul, 130-701, Republic of Korea

    Hye-Sook Seo, Han-Seok Choi, Soon-Re Kim, Youn Kyung Choi, Sang-Mi Woo, Yong Cheol Shin & Seong-Kyu Ko

  2. Department of Life Science, College of Natural Sciences, Hanyang University, Seoul, 133-791, Republic of Korea

    Incheol Shin

  3. Department of Pathology, Tumor Immunity Medical Research Center, Cancer Research Institute, College of Medicine, Seoul National University, Seoul, 110-799, Republic of Korea

    Jong-Kyu Woo

  4. Cancer Preventive Material Development Research Center, College of Oriental Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea

    Sang-Yoon Park

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  1. Hye-Sook Seo
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Seo, HS., Choi, HS., Kim, SR. et al. Apigenin induces apoptosis via extrinsic pathway, inducing p53 and inhibiting STAT3 and NFκB signaling in HER2-overexpressing breast cancer cells. Mol Cell Biochem 366, 319–334 (2012). https://doi.org/10.1007/s11010-012-1310-2

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