Isoalantolactone inhibits IKKβ kinase activity to interrupt the NF‐κB/COX‐2‐mediated signaling cascade and induces apoptosis regulated by the mitochondrial translocation of cofilin in glioblastoma

Xing, Jinyan; Wang, Xun; Lan, Yu‐Long; Lou, Jiacheng; Ma, Binbin; Zhu, Tingzhun; Zhang, Hongqiang; Wang, Dongsheng; Yu, Zhikuan; Yuan, Zhongbo; Li, Xinyu; Zhang, Bo

doi:10.1002/cam4.2013

Cited by 21 publications

(12 citation statements)

References 56 publications

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“…This suggested that alterations in the location of cofilin-1 rather than its expression level were the primary cause of As 2 o 3 -induced apoptosis in NB4-R1 cells, which was consistent with the aforementioned studies (35)(36)(37). Besides, Xing et al (38) demonstrated that isoalantolactone inhibits IKKβ kinase activity and promotes apoptosis of glioblastoma cells by inducing translocation of cofilin-1 to the mitochondria and the release of mitochondrial cytochrome C to the cytoplasm, which activates caspase-3/9. In human leukemia cells, cofilin-1 translocation to the mitochondria could induce mitochondrial injury and cell apoptosis (39).…”

Section: Discussionsupporting

confidence: 82%

Role of cofilin‑1 in arsenic trioxide‑induced apoptosis of NB4‑R1 cells

et al. 2020

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all-trans retinoic acid (aTra) and arsenic trioxide (as 2 o 3) are currently first-line treatments for acute promyelocytic leukemia (APL). However, a number of patients with APL are resistant to ATRA but still sensitive to As 2 o 3 , and the underlying mechanisms of this remain unclear. In the present study, two-dimensional gel electrophoresis, mass spectrometry and other proteomic methods were applied to screen and identify the differentially expressed proteins between the retinoic acid-sensitive cell lines and drug-resistant cell lines. The results demonstrated that in retinoic acid-resistant NB4-R1 cells, the protein expression of cofilin-1 was markedly increased compared with that in the drug-sensitive NB4 cells. Subsequently, the effects of cofilin-1 on As 2 o 3-induced apoptosis in NB4-R1 cells were further investigated. The results revealed that cell viability was markedly suppressed and apoptosis was increased in the As 2 o 3-treated nB4-r1 cells, with increased expression levels of cleaved-poly (ADP-ribose) polymerase and cleaved-caspase 12. Cofilin-1 expression was significantly decreased at both the mRNA and protein levels in the As 2 o 3-treated group compared with the control. Western blotting further revealed that As 2 o 3 treatment decreased the cytoplasmic cofilin-1 level but increased its expression in the mitochondrion. However, the opposite effects of As 2 o 3 on the cytochrome C distribution were found in NB4-R1 cells. This suggested that As 2 o 3 can induce the transfer of cofilin-1 from the cytoplasm to mitochondria and trigger the release of mitochondrial cytochrome C in NB4-R1 cells. Moreover, cofilin-1 knockdown by its specific short hairpin RNA significantly suppressed As 2 o 3-induced NB4-R1 cell apoptosis and inhibited the release of mitochondrial cytochrome C. Whereas, overexpression of cofilin-1 using a plasmid vector carrying cofilin-1 increased the release of cytochrome C into the cytoplasm from the mitochondria in As 2 o 3-treated nB4-r1 cells. In conclusion, cofilin-1 played a role in As 2 o 3-induced NB4-R1 cell apoptosis and it might be a novel target for APL treatment.

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Section: Discussionsupporting

confidence: 82%

Role of cofilin‑1 in arsenic trioxide‑induced apoptosis of NB4‑R1 cells

et al. 2020

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“…Mitochondrial translocation of cofilin induced by cyclohexene was found to be the underlying mechanism of anti-leukemia ( 37 ). Cofilin was confirmed to translocate to the mitochondria after isoalantolactone-induced apoptosis in GBM ( 38 ). These results indicated that mitochondrial translocation of cofilin is pivotal for inducing cell apoptosis.…”

Section: Discussionmentioning

confidence: 98%

Cyclovirobuxine D Induces Apoptosis and Mitochondrial Damage in Glioblastoma Cells Through ROS-Mediated Mitochondrial Translocation of Cofilin

Zhang

Duan

et al. 2021

Front. Oncol.

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BackgroundCyclovirobuxine D (CVBD), a steroidal alkaloid, has multiple pharmacological activities, including anti-cancer activity. However, the anti-cancer effect of CVBD on glioblastoma (GBM) has seldom been investigated. This study explores the activity of CVBD in inducing apoptosis of GBM cells, and examines the related mechanism in depth.MethodsGBM cell lines (T98G, U251) and normal human astrocytes (HA) were treated with CVBD. Cell viability was examined by CCK-8 assay, and cell proliferation was evaluated by cell colony formation counts. Apoptosis and mitochondrial superoxide were measured by flow cytometry. All protein expression levels were determined by Western blotting. JC-1 and CM-H2DCFDA probes were used to evaluate the mitochondrial membrane potential (MMP) change and intracellular ROS generation, respectively. The cell ultrastructure was observed by transmission electron microscope (TEM). Colocalization of cofilin and mitochondria were determined by immunofluorescence assay.ResultsCVBD showed a greater anti-proliferation effect on the GBM cell lines, T98G and U251, than normal human astrocytes in dose- and time-dependent manners. CVBD induced apoptosis and mitochondrial damage in GBM cells. We found that CVBD led to mitochondrial translocation of cofilin. Knockdown of cofilin attenuated CVBD-induced apoptosis and mitochondrial damage. Additionally, the generation of ROS and mitochondrial superoxide was also induced by CVBD in a dose-dependent manner. N-acetyl-L-cysteine (NAC) and mitoquinone (MitoQ) pre-treatment reverted CVBD-induced apoptosis and mitochondrial damage. MitoQ pretreatment was able to block the mitochondrial translocation of cofilin caused by CVBD.ConclusionsOur data revealed that CVBD induced apoptosis and mitochondrial damage in GBM cells. The underlying mechanism is related to mitochondrial translocation of cofilin caused by mitochondrial oxidant stress.

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“…They are often used either as drug leads or as actual drugs. Isoalantolactone (IATL) is a sesquiterpene lactone naturally occurring in the roots of Inula helenium L. IATL has been reported to exert cytotoxic effects against a variety of cancer cells, including pancreatic cancer ( Zhang et al, 2021 ), esophageal cancer ( Lu et al, 2018 ; Wen et al, 2018 ), hepatocellular carcinoma ( Kim et al, 2021 ), prostate cancer ( Rasul et al, 2013 ; Chen et al, 2018 ; Huang et al, 2021 ) and glioblastoma ( Xing et al, 2019 ). The anticancer effects of IATL mainly involve the induction of apoptosis, cell cycle arrest and autophagy ( Weng et al, 2016 ; Chen et al, 2018 ; Lu et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Isoalantolactone Induces Cell Cycle Arrest, Apoptosis and Autophagy in Colorectal Cancer Cells

Zhu

Chen

et al. 2022

Front. Pharmacol.

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Colorectal cancer (CRC) is an aggressive cancer. Isoalantolactone (IATL) has been reported to exert cytotoxicity against various cancer cells, but not CRC. In this study, we explored the anti-CRC effects and mechanism of action of IATL in vitro and in vivo. Our results demonstrated that IATL inhibited proliferation by inducing G0/G1 phase cell cycle arrest, apoptosis and autophagy in CRC cells. Repression of autophagy with autophagy inhibitors chloroquine (CQ) and Bafilomycin A1 (Baf-A1) enhanced the anti-CRC effects of IATL, suggesting that IATL induces cytoprotective autophagy in CRC cells. Mechanistic studies revealed that IATL lowered protein levels of phospho-AKT (Ser473), phospho-mTOR (Ser2448), phospho-70S6K (Thr421/Ser424) in CRC cells. Inhibition of AKT and mTOR activities using LY294002 and rapamycin, respectively, potentiated the inductive effects of IATL on autophagy and cell death. In vivo studies showed that IATL suppressed HCT116 tumor growth without affecting the body weight of mice. In consistent with the in vitro results, IATL lowered protein levels of Bcl-2, Bcl-XL, phospho-AKT (Ser473), phospho-mTOR (Ser2448), and phsopho-70S6K (Thr421/Ser424), whereas upregulated protein levels of cleaved-PARP and LC3B-II in HCT116 tumors. Collectively, our results demonstrated that in addition to inhibiting proliferation, inducing G0/G1-phase cell cycle arrest and apoptosis, IATL initiates cytoprotective autophagy in CRC cells by inhibiting the AKT/mTOR signaling pathway. These findings provide an experimental basis for the evaluation of IATL as a novel medication for CRC treatment.

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Isoalantolactone inhibits IKKβ kinase activity to interrupt the NF‐κB/COX‐2‐mediated signaling cascade and induces apoptosis regulated by the mitochondrial translocation of cofilin in glioblastoma

Cited by 21 publications

References 56 publications

Role of cofilin‑1 in arsenic trioxide‑induced apoptosis of NB4‑R1 cells

Role of cofilin‑1 in arsenic trioxide‑induced apoptosis of NB4‑R1 cells

Cyclovirobuxine D Induces Apoptosis and Mitochondrial Damage in Glioblastoma Cells Through ROS-Mediated Mitochondrial Translocation of Cofilin

Isoalantolactone Induces Cell Cycle Arrest, Apoptosis and Autophagy in Colorectal Cancer Cells

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