Abstract
BackgroundThe 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.MethodsThe 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.ResultsThe 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.ConclusionOur data demonstrated, for the first time, that CA might represent a novel drug candidate for the development of an anti-CRPC therapy.
Highlights
The development of potent non-toxic chemotherapeutic drugs against castration resistant prostate cancer (CRPC) remains a major challenge
The results suggested that Prostate cancer (PCa) cell viability was efficiently inhibited after Corosolic acid (CA) treatment for 24 and 48 h and the inhibition rates were both concentration- and time-dependent
Downregulation of AKT phosphorylation seems to be a secondary event associated with the Protein kinase RNA-like endoplasmic reticulum kinase (PERK)/CCAAT-enhancer-binding protein homologous protein (CHOP)/Tribbles 3 (TRIB3) pathway activation To delineate the relationship between endoplasmic reticulum (ER) stress and AKT in CA-induced apoptosis, we examined tribbles homolog 3 (TRIB3) gene and protein expression (CHOP downstream target gene) by RT-PCR and western blot after exposure of human PCa cells to CA (5, 10 and 15 μM) for 24 h
Summary
The development of potent non-toxic chemotherapeutic drugs against castration resistant prostate cancer (CRPC) remains a major challenge. CA anti-prostate cancer activities and mechanisms, in CRPC, are not clearly understood. Many PCa patients have HDPC, the vast majority of them become hormonal refractory PCa (HRPC) or castration-resistant PCa (CRPC) patients after 18 to 24 months [1, 2]. CRPC has become one of the difficult problems for urologists and oncologists due to its high metastatic potential, resistance to chemotherapeutic agents and easy relapse. It remains one of the main causes of high mortality in PCa patients. There is a desperate need to discover efficient drugs to treat PCa, in particular those which are effective against CRPC
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