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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.