Beta-Elemonic Acid Inhibits Growth And Triggers Apoptosis In Human Castration-Resistant Prostate Cancer Cells Through The Suppression Of Jak2/ Stat3/Mcl-1 And Nf-Xb Signal Pathways
CHEMICO-BIOLOGICAL INTERACTIONS(2021)
Abstract
Castration-resistant prostate cancer (CRPC) has become a significant problem in the current treatment of prostate cancer (PCa) with the characteristics of high metastatic potential, resistance and easy recurrence. The abnormal activation of JAK2/STAT3/MCL-1 and NF-kappa B has been confirmed as the main reason for the development of CRPC. We previously found that beta-elemonic acid (beta-EA) as a natural triterpene has potential anti-inflammatory and anti-osteosarcoma effects with lower toxicity. But it remains unknown whether it had effects on CRPC. The present research in vitro and in vivo systematically investigates anti-cancer effects and mechanisms of beta-EA on human CRPC. beta-EA treatment resulted in apoptotic cell death in human PCa cells by mitochondrial apoptotic pathways (including up-regulation of cleaved caspase-3, cleaved PARP, and Bax or down-regulation of Bcl-2). Besides, beta-EA at relatively lower levels inhibited colony-forming, the migration and invasion potential of PCa cells, indicating its anti-proliferation and anti-metastasis activities. After exploring the potential mechanism, our results suggested that it subsequently inhibited the activation of JAK2/STAT3/MCL-1 and NF-kappa B signaling pathway by the administration of beta-EA. The silencing of NF-kappa B/p65, JAK2 and STAT3, respectively, increased the sensitivity of the PCa cells to beta-EA induced apoptosis. Moreover, beta-EA exhibited a strong affinity with its essential proteins JAK2, RELA/p65, NF-kappa BI alpha/I kappa B alpha by molecular docking analysis. Importantly, beta-EA retards tumor growth in a murine xenograft model, consistent with our study in vitro. Taken together, findings from this study reveal for the first time the potential role and mechanisms of beta-EA on CRPC.
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Key words
β, -elemenic acid (β, -EA), JAK2, STAT3, MCL-1, NF-κ, B, Castrate-resistant prostate cancer (CRPC), Apoptosis, Molecular docking
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