Connexin 43 upregulation by dioscin inhibits melanoma progression via suppressing malignancy and inducing M1...

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Connexin 43 (Cx43) is a gap junction protein crucial in the tumor microenvironment (TME) and a potential target for melanoma therapy.
• Dioscin, a steroidal saponin, exhibits anti-tumor properties, but its mechanism of action remains largely unknown.

Purpose of the Study:

• To investigate the anti-tumor mechanism of dioscin in melanoma, focusing on its interaction with Cx43.
• To evaluate dioscin's effects on melanoma cell malignancy, cancer stem cell markers, epithelial-to-mesenchymal transition (EMT), and the tumor-associated macrophage (TAM) phenotype.

Main Methods:

• Western blotting (WB), Flow cytometry (FACS), and immunofluorescence were used to assess Cx43 expression and function.
• In vitro studies utilized B16 melanoma cells and RAW264.7 macrophages.
• In vivo experiments involved two classical animal models of melanoma metastasis.

Main Results:

• Dioscin activated Cx43 transcription and translation via the retinoic acid signaling pathway, enhancing its function and suppressing melanoma cell migration and invasion.
• Dioscin reduced cancer stem cell pluripotency markers and EMT, while promoting M2-to-M1 phenotype transition in TAMs, enhancing their phagocytic activity.
• In vivo, dioscin demonstrated significant anti-metastatic effects, correlated with Cx43 expression in tumors and metastatic sites.

Conclusions:

• Dioscin effectively targets Cx43 to inhibit melanoma cell malignancy and modulate the tumor microenvironment by activating macrophage sensitivity.
• Dioscin presents a promising therapeutic strategy for melanoma by targeting both tumor cells and the immune microenvironment.