Tetrandrine induces cell cycle arrest in cutaneous melanoma cells by inhibiting IL-6/CDC42 signaling.

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.