Terphenyllin induces CASP3-dependent apoptosis in A375 cells through upregulation of P53

Abstract Melanoma, the deadliest form of skin cancer, can develop in any area where melanocytes are present. Currently, platinum-based chemotherapeutic drugs such as cisplatin are commonly used for anti-tumor treatment. However, these drugs often result in significant cytotoxicity, highlighting the need for more effective and less toxic alternatives. Terphenyllin (TER) is a natural compound derived from the coral fungus Aspergillus candidus. Our results demonstrated that TER notably induces apoptosis while exhibiting lower cytotoxicity than does cisplatin at equivalent doses. We observed an upregulation of P53 expression in A375 cells following TER treatment, accompanied by the cleavage of CASP3, GSDME, and PARP1. Upregulated P53 led to increased expression of FAS/BAX and elevated expression of BAX, which prompted the release of cytochrome c from mitochondria to the cytoplasm, ultimately triggering CASP3 cleavage. By knocking out CASP3, TER-induced GSDME cleavage was alleviated and TER-induced A375 cells were shift from apoptosis to necrosis. Additionally, our investigation of the role of GSDME in TER-induced cell death revealed that knockout of GSDME significantly enhanced TER-induced apoptosis and reduced LDH release during induction. Our study demonstrated that TER promotes apoptosis in A375 cells through the P53-BAX-CASP3 pathway. Furthermore, the upregulation of P53 blocks the cell cycle in S-phase by inhibiting CyclinA2 expression. This dual effect eradicates melanoma cells by promoting apoptosis and inhibiting proliferation simultaneously. In summary, our research provides insights into the molecular mechanisms underlying the action of TER on melanoma cells. These findings may have important implications for the development of novel antimelanoma therapeutics.