Patchouli alcohol suppresses castration-resistant prostate cancer progression by inhibiting NF-kappa B signal pathways

TRANSLATIONAL ANDROLOGY AND UROLOGY(2022)

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摘要
Background: There is evidence that patchouli alcohol (PA) has cytotoxic effects on human cancer cell lines, including inhibiting cell growth, migration, and invasion. However, the exact molecular mechanism of PA in human castration-resistant prostate cancer (CRPC) cells remains unclear. Methods: DU145 and PC-3 cells were treated with different concentrations of PA for 48 h. Cell counting kit-8 (CCK-8), colony formation, and 5-ethynyl-2'-deoxyuridine (EdU) staining were used to detect cell proliferation. Scratch tests and transwell assays were used to detect cell migration and invasion. TdT-mediated dUTP nick-end labeling (TUNEL) staining and flow cytometry were performed to examine apoptosis and mitochondrial membrane potential. The expression of the apoptosis- and migration-related proteins and the phosphorylation of the nuclear factor kappa -B (NF-kappa B) cells were detected by Western blot. A chromatin immunoprecipitation (ChIP) analysis was conducted to examine NF-kappa B p65 binding to the myeloid cell leukemia-1 (Mcl-1) promoter. A xenograft model of nude mice was established to verify the anticancer effects of PA in vivo. Results: PA inhibited the proliferation, migration, and invasion, and induced the apoptosis of the DU145 and PC-3 cells in a concentration-dependent manner, and was accompanied by mitochondrial membrane potential depolarization, the upregulation of cleaved caspase-3, cleaved poly ADP-ribose polymerase (PARP) and Bcl-2-associated X protein (Bax), and the downregulation of B-cell lymphoma-2 (Bcl-2), Ki67, and Mcl-1. In relation to the mechanism, PA significantly downregulated the phosphorylation of inhibitor of NF-kappa B alpha (I kappa B alpha) and p65 and the expression of matrix metalloprotein (MMP)-2, MMP-7, MMP-9, and vascular endothelial growth factor (VEGF). PA prevented p65 binding to the Mcl-1 promoter by inactivating NF-kappa B p65, downregulated the transcription of Mcl-1, and the silencing of p65 increased the sensitivity of the CRPC cells to PA-induced apoptosis. The overexpression of Mcl-1 significantly reversed the PA-induced apoptosis of the CRPC cells. Additionally, consistent with our in-vitro study, PA inhibited tumor growth in the mouse xenograft model. Conclusions: We found that PA inhibits the growth, migration, and invasion of CRPC cells in vitro and in vivo by inducing an apoptosis mechanism and inhibiting NF-kappa B activity. Our findings may provide therapeutic targets for this malignant tumor.
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关键词
Patchouli alcohol (PA), castration-resistant prostate cancer (CRPC), nuclear factor kappa-B (NF-kappa B), Mcl-1, apoptosis
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