Isoalantolactone induces apoptosis through ROS-mediated ER stress and inhibition of STAT3 in prostate cancer cells

Abstract

BackgroundProstate cancer is one of the most commonly diagnosed cancers in men worldwide. Currently available therapies for metastatic prostate cancer are only marginally effective. Therefore, new therapeutic agents are urgently needed to improve patient outcome. Isoalantolactone (IATL), an active sesquiterpene naturally present in many vegetables and medicinal plants, is known to induce cell death and apoptosis in various cancer cell lines. Nevertheless, antitumor mechanisms initiated by IATL in cancer cells have not been fully defined.MethodsCell apoptosis and cellular ROS levels were analyzed by flow cytometry. Western blot and qRT-PCR were used to analyze the protein and mRNA levels of indicated molecules, respectively. Nude mice xenograft model was used to test the effects of IATL on prostate cancer cell growth in vivo.ResultsIn this study, we found that IATL dose-dependently inhibited cancer cell growth and induced apoptosis in PC-3 and DU145 cells. Mechanistically, our data found that IATL induced reactive oxygen species (ROS) production, resulting in the activation of endoplasmic reticulum stress pathway and eventually cell apoptosis in prostate cancer cells. IATL also decreased the protein expression levels of p-STAT3 and STAT3, and the effects of IATL were reversed by pretreatment with N-acetyl-L-cysteine (NAC). In vivo, we found that IATL inhibited the growth of prostate cancer xenografts without exhibiting toxicity. Treatment of mice bearing human prostate cancer xenografts with IATL was also associated with induction of ER stress and inhibtion of STAT3.ConclusionIn summary, our results unveil a previously unrecognized mechanism underlying the biological activity of IATL, and provide a novel anti-cancer candidate for the treatment of prostate cancer.

Roles of Reactive Oxygen Species in Biological Behaviors of Prostate Cancer

“…Severe ER stress has the ability to initiate another atypical intrinsic apoptosis response [ 200 ]. Induction of ER stress activation and PCa cell apoptosis by both Chelerythrine (CHE) and Isoalantolactone (IALT) is dependent on ROS generation [ 193 , 201 ]. Mechanically, IALT increases the levels of ROS-dependent p-eIF2 α and ATF4 in the PC-3 and DU145 cells, thus stimulating expression of the transcription factor CHOP that inhibits the expression of Bcl-2 and is strictly responsible for the initiation of the cell apoptosis cascade [ 201 – 203 ].…”

“…Induction of ER stress activation and PCa cell apoptosis by both Chelerythrine (CHE) and Isoalantolactone (IALT) is dependent on ROS generation [ 193 , 201 ]. Mechanically, IALT increases the levels of ROS-dependent p-eIF2 α and ATF4 in the PC-3 and DU145 cells, thus stimulating expression of the transcription factor CHOP that inhibits the expression of Bcl-2 and is strictly responsible for the initiation of the cell apoptosis cascade [ 201 – 203 ]. Mitochondrial outer membrane permeabilization (MOMP) also results in elevated cytoplasmic proapoptotic molecules containing apoptosis-inducing factor (AIF) and endonuclease G (Endo G) in response to organelle damage induced by ROS, and these molecules function in a caspase-independent manner [ 204 ].…”

Anti-Tumor Effect and Mechanism of Parthenolide in Gastric Cancer Cellline BGC-823

“…Promote its transcription [30]. The results showed that the STAT3 phosphorylation was decreased, indicating that PN can block the phosphorylation of STAT3, thereby preventing its entry into the nucleus.…”

Assessment of NR4A Ligands that Directly Bind and Modulate the Orphan Nuclear Receptor Nurr1

“…Celastrol, which contains a reactive quinone methide moiety enabling covalent attachment to cysteine residues (49), including direct binding and inhibition of c-Myc-Max heterodimers (50), cancerous inhibitor of protein phosphatase 2A (CIP2A) (51), STAT3 (52), SHOC-2 to inhibit ERK signaling (53), IKKα and IKKβ (54), and HSP90-chaperone interactions (55-57); directly binds nearly 70 protein targets in a proteome microarray assay (53); and affects other cellular signaling pathways including protein phosphatase 2A-Akt, AMPK, and WNT/β-catenin (58). Isoalantolactone activates AMPKα (28) and inhibits STAT3 (59) and IKKβ (60). Camptothecin inhibits topoisomerase I (61).…”