9-Methoxycamptothecin induces proliferating cell nuclear antigen associated factor 15 mediated proliferation inhibition, DNA damage, and apoptosis in melanoma cells

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Melanoma is one of the most lethal forms of skin cancer, driving continuous research efforts to discover effective therapeutic strategies. Phytochemicals are promising for antimelanoma drug development because of their multitarget bioactivities. 9-Methoxycamptothecin (MCPT), a plant-origin compound, has demonstrated potent anticancer activity against various human cancers; however, its inhibitory effects on melanoma and the underlying molecular mechanisms remain incompletely understood. In this research, human melanoma cell lines (A375, SKMEL28) were treated with MCPT. Cell proliferation was evaluated using MTT and clonogenic assays. Cell cycle and apoptosis were assessed by flow cytometry. The MCPT-induced DNA damage in melanoma cells was observed via immunofluorescence staining of γ-H2AX. Protein expression was analyzed by western blotting. Proliferating cell nuclear antigen associated factor 15 (PAF15) was overexpressed via lentiviral transduction to evaluate its functional role in MCPT response. The antimelanoma effect of MCPT in vitro was studied in BALB/c nude mice bearing subcutaneous tumors from A375 cells. The results showed that MCPT suppressed melanoma cell proliferation via inducing the G2/M phase cell cycle arrest. Meanwhile, MCPT induces caspase-dependent apoptosis and DNA damage in melanoma cells. In vivo , MCPT effectively inhibited the growth of melanoma xenografts. Crucially, these MCPT-mediated effects were partly rescued by exogenous PAF15 overexpression. In conclusion, MCPT exerts antimelanoma effects by inhibiting proliferation, inducing cell cycle arrest, DNA damage, and apoptosis. Importantly, these effects are critically mediated through the downregulation of PAF15.

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