LukS-PV inhibits the proliferation of hepatocellular carcinoma cells by maintaining FOXO3 stability via the PI3K/AKT signaling pathway.

Hepatocellular carcinoma(HCC) is one of the common malignant tumors. LukS-PV is the S component of Panton-Valetine leukocidin(PVL) secreted by Staphylococcus aureus. Forkhead box O3 (FOXO3) is a member of the FOXO subfamily of transcription factors that acts as a tumor suppressor. In this study, we investigated the role of LukS-PV on the proliferation of HCC and explored possible mechanisms. We treated HCC cells with various concentrations of LukS-PV and evaluated the effect of LukS-PV on cell viability using the cell counting kit-8 and colony formation assays. Real-time PCR and western blot assays were used to analyze mRNA and protein expression levels, respectively. Immunofluorescence staining was performed to examine the intracellular localization of FOXO3. The expression of FOXO3 and its downstream target genes were analyzed by immunohistochemical staining. The protein synthesis inhibitor cycloheximide and the proteosome inhibitor MG132 were used to explore the potential mechanisms by which LukS-PV regulated FOXO3. We demonstrated that LukS-PV inhibited the proliferation of HCC cells in a concentration dependent manner. LukS-PV upregulated FOXO3 expression both in vitro and in vivo. Moreover, LukS-PV facilitated the entry of FOXO3 into the nucleus and, subsequently, regulated the transcription of downstream target genes. In addition, we discovered that LukS-PV decreased the expression of phosphorylated FOXO3 through the PI3K/AKT signaling pathway and maintained FOXO3 protein stability via the ubiquitin-proteasome pathway. Taken together, our data indicated that LukS-PV exert anticancer activities through FOXO3. LukS-PV may be a promising candidate for HCC treatment.