P38α MAPK mediates 17β-estradiol inhibition of MMP-2 and -9 expression and cell migration in human lovo colon cancer cells

Hsi Hsien Hsu, Chung Jung Liu, Chia Yao Shen, Yi Jyun Chen, Li Mien Chen, Wu Hsien Kuo, Yueh Min Lin, Ray Jade Chen, Chang Hai Tsai, Fuu Jen Tsai, Chih Yang Huang

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Abstract

Epidemiological studies demonstrate that the incidence and mortality rates of colorectal cancer in women are lower than in men. However, it is unknown if 17β-estradiol (E2) treatment is sufficient to inhibit cell proliferation and cell migration in human colon cancer cells. Up-regulation of urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), and matrix metallopeptidases (MMPs) is reported to associate with the development of cancer cell mobility, metastasis, and subsequent malignant tumor. In the present study, we treated human LoVo colon cancer cells with E2 to explore whether E2 down-regulates cell proliferation and migration, and to identify the precise molecular and cellular mechanisms behind the down-regulatory responses. Here, we found that E2 treatment decreased cell proliferation and cell cycle-regulating factors such as cyclin A, cyclin D1 and cyclin E. At the same time, E2 significantly inhibited cell migration and migration-related factors such as uPA, tPA, MMP-2, and MMP-9. However, E2 treatment showed no effects on upregulating expression of plasminogen activator inhibitor-1 (PAI-1), tissue inhibitor of metalloproteinase-1, -2, -3, and -4 (TIMP-1, -2, -3, and -4). After administration of inhibitors including QNZ (NFκB inhibitor), LY294002 (Akt activation inhibitor), U0126 (ERK1/2 inhibitor), SB203580 (p38 MAPK inhibitor) or SP600125 (JNK1/2 inhibitor), E2-downregulated cell migration and expression of MMP-2 and MMP-9 in LoVo cells is markedly inhibited only by p38 MAPK inhibitors, SB203580. Application of specific target gene siRNA (ERα, ERβ, p38α, and p38β) to LoVo cells further confirmed that p38 MAPK mediates E2/ERs inhibition of MMP-2 and -9 expression and cell motility in LoVo cells. Collectively, these results suggest that E2 treatment down-regulates cell proliferation by modulating the expression of cyclin A, cyclin D1 and cyclin E. E2 treatment simultaneously impaired cell migration by inhibiting the expression of uPA, tPA, MMP-2, and MMP-9 through E2/ERs-p38α MAPK signaling pathway in human LoVo colon cancer cells.

Original languageEnglish
Pages (from-to)3648-3660
Number of pages13
JournalJournal of Cellular Physiology
Volume227
Issue number11
DOIs
Publication statusPublished - Nov 2012

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ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

Cite this

Hsu, H. H., Liu, C. J., Shen, C. Y., Chen, Y. J., Chen, L. M., Kuo, W. H., Lin, Y. M., Chen, R. J., Tsai, C. H., Tsai, F. J., & Huang, C. Y. (2012). P38α MAPK mediates 17β-estradiol inhibition of MMP-2 and -9 expression and cell migration in human lovo colon cancer cells. Journal of Cellular Physiology, 227(11), 3648-3660. https://doi.org/10.1002/jcp.24072