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

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.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0889-x) contains supplementary material, which is available to authorized users.

Cell death induced by the ER stressor thapsigargin involves death receptor 5, a non-autophagic function of MAP1LC3B, and distinct contributions from unfolded protein response components

“…5a; see Additional file 5: Figure S13B for knockdown efficiency). A pro-death role for IRE1 has previously been suggested via signaling to JNK [39,[52][53][54], and JNK is required for Tg-induced cell death in LNCaP cells [7]. In agreement, the JNK inhibitor JNK-IN-8 efficiently diminished Tg-induced cell death (Fig.…”

“…9). This may at least in part explain why IRE1 is found to be required for ER stress-induced cell death in some cell types [49,53,54] while having no effect on cell death in others [18,[92][93][94]. We could not observe any pro-survival effect of IRE1 or XBP1 during Tg-induced cell death in the cell lines we examined.…”

“…However, another study proposed that specific IRE1 RIDD activity towards DR5 mRNA opposes ER stress-induced cell death [9]. Finally, a number of studies suggest that IRE1 can contribute to ER stress-induced cell death via activation of JNK [39,[52][53][54]. Contrasting results have been reported with regard to the overall, net effect of IRE1 on ER stress-induced cell death [9,18,49], and opposing results obtained with the same ER stressor (Tg) in different cell lines [9,18,49] suggest a cell type-dependent role of IRE1.…”

Natural Products Targeting ER Stress, and the Functional Link to Mitochondria

“…In particular, IRE1 binds TRAF2, determining ASK1 phosphorylation and JNK phosphorylation, causing the activation of mitochondrion-dependent intrinsic apoptotic pathway. Moreover, corosolic acid activated the PERK-eIF2a-ATF4 pathway, leading to the pro-apoptotic CHOP up-regulation by inhibition of anti-apoptotic kinase AKT [39]. 20(S)-Protopanaxadiol, a triterpene aglycone of the glycosides occurring in Panax ginseng (Araliaceae) known as ginsenosides, inhibited cell growth and induced apoptosis in human hepatocarcinoma HepG2 cells.…”

STAT3 signaling in ovarian cancer: a potential therapeutic target

“…Corosolic acid, a natural triterpenoid compound derived from banaba leaves and apples, has been shown to have anti-tumor effects on a variety of tumor models, such as glioblastoma 118 , prostate cancer 119,120 , retinoblastoma 121 , renal carcinoma 122 , gastric cancer 123 , breast cancer 124 , liver cancer 125,126 , colon cancer 127 , lung adenocarcinoma 128 , cervix adenocarcinoma 129 , osteosarcoma 130,131 . Similar to curcumin and resveratrol, CA is a potent STAT3 inhibitor, suppressing cell growth of ovarian cancer and glioblastoma by abrogating STAT3 activity 118,132 .…”