Journal Article

Corosolic acid, a natural triterpenoid, induces ER stress-dependent apoptosis in human castration resistant prostate cancer cells via activation of IRE-1/JNK, PERK/CHOP and TRIB3

Zhao, Ang, Li, Lin, Zhang, Qi, Wang, Yu, Ma, Bo, Sun, Yang, Zhang, Hang, Zhu, Zhiming, Bao, Xiaowen

2018

Overview

Background The development of potent non-toxic chemotherapeutic drugs against castration resistant prostate cancer (CRPC) remains a major challenge. Corosolic acid (CA), a natural triterpenoid, has anti-cancer activity with limited side effects. However, CA anti-prostate cancer activities and mechanisms, particularly in CRPC, are not clearly understood. In this study, we investigated CA anti-tumor ability against human CRPC and its mechanism of action. Methods The cell apoptosis and proliferation effects were evaluated via MTT detection, colony formation assay and flow cytometry. Western blot, gene transfection and immunofluorescence assay were applied to investigate related protein expression of Endoplasmic reticulum stress. A xenograft tumor model was established to investigate the inhibitory effect of CA on castration resistant prostate cancer in vivo. Results The results showed that CA inhibited cell growth and induced apoptosis in human prostate cancer cell (PCa) line PC-3 and DU145, as well as retarded tumor growth in a xenograft model, exerting a limited toxicity to normal cells and tissues. Importantly, CA activated endoplasmic reticulum (ER) stress-associated two pro-apoptotic signaling pathways, as evidenced by increased protein levels of typical ER stress markers including IRE-1/ASK1/JNK and PERK/eIF2α/ATF4/CHOP. IRE-1, PERK or CHOP knockdown partially attenuated CA cytotoxicity against PCa cells. Meanwhile, CHOP induced expression increased Tribbles 3 (TRIB3) level, which lead to AKT inactivation and PCa cell death. CHOP silencing resulted in PCa cells sensitive to CA-induced apoptosis. Conclusion Our data demonstrated, for the first time, that CA might represent a novel drug candidate for the development of an anti-CRPC therapy.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Acids / Antifungal agents / Apoptosis / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cancer therapies / Care and treatment / Castration resistant PCa (CRPC) / CCAAT-enhancer-binding protein homologous protein (CHOP) / Cell growth / Cell proliferation / Corosolic acid (CA) / Diabetes / Drugs / Endoplasmic reticulum / Endoplasmic reticulum stress (ER stress) / Gastric cancer / Glucose / Immunology / Kinases / Oncology / Patient outcomes / Phosphorylation / Prostate cancer / Protein kinase RNA-like endoplasmic reticulum kinase (PERK) / Proteins / Stress response / Transcription factors / Tribbles homolog 3 (TRIB3)