β-elemonic acid inhibits growth and triggers apoptosis in human castration-resistant prostate cancer cells through the suppression of JAK2/STAT3/MCL-1 and NF-ĸB signal pathways.

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-κB has been confirmed as the main reason for the development of CRPC. We previously found that β-elemonic acid (β-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 β-EA on human CRPC. β-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, β-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-κB signaling pathway by the administration of β-EA. The silencing of NF-κB/p65, JAK2 and STAT3, respectively, increased the sensitivity of the PCa cells to β-EA induced apoptosis. Moreover, β-EA exhibited a strong affinity with its essential proteins JAK2, RELA/p65, NF-κBIα/IκBα by molecular docking analysis. Importantly, β-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 β-EA on CRPC.

• Authors: Xiaowen Bao, Jianwei Zhu, Chaoxing Ren, Ang Zhao, Mingya Zhang, Zhiming Zhu, Xuanzhao Lu, Yuning Zhang, Xiaotian Li, Xinyu Sima, Jiaqi Li, Qi Zhang, Bo Ma
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 342 Pg. 109477 (Jun 01 2021) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 33878321 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• MCL1 protein, human
• Myeloid Cell Leukemia Sequence 1 Protein
• NF-kappa B p50 Subunit
• NFKB1 protein, human
• STAT3 Transcription Factor
• STAT3 protein, human
• Triterpenes
• beta-elemonic acid
• JAK2 protein, human
• Janus Kinase 2

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Humans
• Janus Kinase 2 (metabolism)
• Male
• Mice, Inbred BALB C
• Myeloid Cell Leukemia Sequence 1 Protein (metabolism)
• NF-kappa B p50 Subunit (metabolism)
• Prostatic Neoplasms, Castration-Resistant (drug therapy)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects)
• Triterpenes (pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays
• Mice