TY - JOUR
T1 - P38α MAPK mediates 17β-estradiol inhibition of MMP-2 and -9 expression and cell migration in human lovo colon cancer cells
AU - Hsu, Hsi Hsien
AU - Liu, Chung Jung
AU - Shen, Chia Yao
AU - Chen, Yi Jyun
AU - Chen, Li Mien
AU - Kuo, Wu Hsien
AU - Lin, Yueh Min
AU - Chen, Ray Jade
AU - Tsai, Chang Hai
AU - Tsai, Fuu Jen
AU - Huang, Chih Yang
PY - 2012/11
Y1 - 2012/11
N2 - 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.
AB - 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.
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U2 - 10.1002/jcp.24072
DO - 10.1002/jcp.24072
M3 - Article
C2 - 22377968
AN - SCOPUS:84864083373
SN - 0021-9541
VL - 227
SP - 3648
EP - 3660
JO - Journal of Cellular Physiology
JF - Journal of Cellular Physiology
IS - 11
ER -