Abstract |
Thymosin beta4 (Tbeta4) is a major actin-sequestering protein that has been implicated in the growth, survival, motility, and metastasis of certain tumors and is considered an indicator for malignant progression. Therefore, identifying compounds that can downregulate Tbeta4 expression is very important for the development of anti- cancer chemotherapies. In this study, we investigated the effects of elevated cAMP on Tbeta4 expression and the metastatic potential of murine B16 melanoma cells. In addition, we also dissected the mechanism underlying cAMP-mediated Tbeta4 suppression. We found that treatment with the cAMP-inducing compounds alpha-MSH ( alpha-melanocyte stimulating hormone) and IBMX (3-isobutyl-1-methylxanthine) significantly suppressed Tbeta4 expression and regulated EMT-associated genes through the suppression of NF-kappaB activation in B16F10 cells. Along with decreased Tbeta4 expression, the in vitro invasiveness and anchorage-independent growth in a semi-solid agar of these cells were also inhibited. In animal experiments, the metastatic potential of the alpha-MSH- or IBMX-treated B16F10 melanoma cells was decreased compared to untreated control cells. Collectively, our data demonstrate that elevated intracellular cAMP significantly suppresses Tbeta4 expression and reduces MMP-9 activity, which leads to decreased metastatic potential. Moreover, suppression of NF-kappaB activation by alpha-MSH or IBMX is critical for inhibiting Tbeta4 expression.
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Authors | Aeyung Kim, Minsik Son, Keun Il Kim, Young Yang, Eun Young Song, Hee Gu Lee, Jong-Seok Lim |
Journal | Experimental cell research
(Exp Cell Res)
Vol. 315
Issue 19
Pg. 3325-35
(Nov 15 2009)
ISSN: 1090-2422 [Electronic] United States |
PMID | 19500569
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- NF-kappa B
- thymosin beta(4)
- Thymosin
- Cyclic AMP
- Matrix Metalloproteinase 9
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Topics |
- Animals
- Cell Proliferation
- Cells, Cultured
- Cyclic AMP
(agonists, physiology)
- Gene Expression Regulation, Neoplastic
- Matrix Metalloproteinase 9
(metabolism)
- Melanoma
(metabolism, pathology)
- Melanoma, Experimental
(metabolism, pathology)
- Mice
- NF-kappa B
(metabolism)
- Neoplasm Metastasis
- Thymosin
(antagonists & inhibitors, genetics)
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