Melanoma is the leading cause of skin cancer-related death. The STAT3 (signal transducer and activator of transcription 3) and TLR4 (toll-like receptor 4) signaling pathways have been shown to be activated in melanoma. Activation of each of the two pathways can promote melanoma growth, angiogenesis and metastasis. Suppressing TLR4 or STAT3 signaling has been proposed as a novel approach for melanoma management. Nevertheless, the TLR4/STAT3 pathway has not yet been established in melanoma. Atractylodis Macrocephalae Rhizoma (Baizhu in Chinese), a Qi-tonifying Chinese medicinal herb, is commonly prescribed by Chinese medicine doctors for treating melanoma. We have demonstrated that atractylenolide II (AT-II), isolated from Baizhu, could induce apoptosis, and inhibit proliferation and migration in melanoma cells. AT-II was also shown to be able to significantly inhibit murine melanoma growth and metastasis at non-toxic doses in mice. In both mouse melanoma tissues and cultured melanoma cells, AT-II potently suppressed STAT3 activation. AT-II also inhibited bacterial lipopolysaccharide (LPS, a specific TLR4 ligand) triggered activation of STAT3 in melanoma cells. Molecular docking showed that AT-II could bind to the TLR4/MD-2 receptor complex; and in melanoma cells, AT-II could reduce the binding of LPS to TLR4. Treatment of MPLAs (synthetic monophosphoryl lipid A, a TLR4 agonist) or overexpression of STAT3C (a dominant-active variant of STAT3) diminished AT-II-afforded anti-proliferative and anti-invasive effects in melanoma cells. We, therefore, hypothesize that suppression of TLR4/STAT3 signaling contributes to the antimelanoma effects of AT-II. To address this hypothesis, we propose to: 1) establish the TLR4/STAT3 pathway in melanoma cells; 2) determine how the TLR4/STAT3 pathway is inhibited by AT-II in melanoma cells; and 3) determine the contribution of TLR4/STAT3 signaling inhibition in the antimelanoma effects of AT-II in vitro and in vivo. The outcome of this study should advance our understanding of the antimelanoma mechanisms of AT-II and provide a chemical and pharmacological justification for the clinical application of Baizhu in melanoma management. This contribution will be significant because it is one step in a continuum of research that is expected to lead to future clinical trials of AT-II as a novel antimelanoma agent.
|Effective start/end date||1/12/16 → 30/11/18|
UN Sustainable Development Goals
In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This project contributes towards the following SDG(s):
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