Elucidating the role of TLR4/STAT3 signaling in the antimelanoma effects of atractylenolide II

Melanoma is the leading cause of skin cancer-related death. Researchers have found that activating TLR4 (toll-like receptor 4) signalling can promote melanoma growth and spread. However, the mechanisms by which TLR4 signalling drives melanoma progression remain unclear. STAT3 (signal transducer and activator of transcription 3) is a transcription factor that transcribes various oncogenes to accelerate tumour progression. EGFR (epidermal growth factor receptor) is a known upstream receptor kinase of STAT3, and its activation has been shown to interact with TLR4 signalling. In this study, we found that TLR4 signalling can activate the EGFR/STAT3 pathway in melanoma. Moreover, inactivating STAT3 in melanoma cells can significantly reduce TLR4 signalling-accelerated tumour growth, suggesting that activation of STAT3 is a key event in TLR4 signalling-mediated melanoma progression. Additionally, we discovered that the EGFR ligand EGF can bind MD2, the co-receptor of TLR4, and then activate TLR4/MD2 signalling, indicating that EGF is a common ligand of TLR4/MD2 and EGFR. Collectively, these findings provide new insights into melanoma pathogenesis.

Atractylodis Macrocephalae Rhizoma (Baizhu in Chinese) is a Chinese medicinal herb commonly used to treat cancers including melanoma. Atractylenolide II (AT-II), a sesquiterpene compound from Baizhu, shows potential as an anticancer agent with high oral availability. We found that AT-II effectively suppresses melanoma tumour growth in mice without causing significant toxicity. Mechanistic studies revealed that AT-II can bind both TLR4/MD2 complex and EGFR to inhibit STAT3 activation, and inhibition of STAT3 signalling contributes to the anti-melanoma effects of AT-II. These findings support the traditional use of Baizhu in treating melanoma and lay the groundwork for developing AT-II as a novel, effective, and safe melanoma agent.

Additionally, we found that blocking both TLR4/MD2 and EGFR pathways at the same time has a powerful anticancer effect on various types of cancer cells. This suggests a new therapeutic strategy for cancer treatment that involves dual inhibition of these two pathways. We have submitted a U.S. provisional patent application (application No: 63679205) for this dual-target inhibition anticancer strategy.

In summary, this project helps us better understand the pathogenesis of melanoma and supports the development of AT-II as a promising anti-melanoma agent. Furthermore, it proposes a novel anticancer strategy involving the dual inhibition of TLR4/MD2 and EGFR signalling, which could lead to the development of innovative anticancer drugs.

Project Investigator