Background: Cutaneous melanoma (CM) is a skin melanocytes-derived malignant tumor accounting for most of the death in skin cancers. The clinical drug for CM is limited or with poor efficacy. Tetrandrine is a natural alkaloid with diverse pharmacological effects including anti-cancer. This study investigated the anti-cancer potential and mechanisms of tetrandrine in CM, which might provide more therapeutic options for CM.
Methods: The effects of tetrandrine on CM cell proliferation were evaluated via CCK8 and colony formation assay. The cell cycle analysis was conducted by flow cytometry. qRT-PCR and western blotting were performed to determine relevant RNA and protein levels. Co-Immunoprecipitation assay was used to detect the protein-protein interaction. Small interfering RNA transfection or lentiviral transduction were used to knockdown or overexpress target proteins, respectively.
Results: Tetrandrine triggered a significant G0/G1 cell cycle arrest in A375 and SK-MEL-2 cells. Tetrandrine decreased the expression of the cell cycle activator cyclin D1 and increased cell cycle inhibitor p21. In-depth study revealed that the anti-CM activities of tetrandrine mainly dependent on Interleukin-6 (IL-6) and cell division cycle 42 (CDC42) regulation. A direct interaction between IL-6 and CDC42 was identified. Tetrandrine suppressed IL-6 expression and subsequently inhibited CDC42, which in turns lead to G0/G1 cell cycle arrest in CM cells.
Conclusion: Tetrandrine suppressed CM cell growth by triggering G0/G1 cell cycle arrest via IL-6/CDC42 inhibition. Tetrandrine should be a promising compound for CM treatment.
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