Xanthatin induces apoptosis by activating endoplasmic reticulum stress in hepatoma cells

Shi, Tianlu; Zhang, Lei; Cheng, Qiyao; Yu, Jishuang; Li, Jun; Shen, Yujun; Feng, Xiaohai

doi:10.1016/j.ejphar.2018.10.041

Cited by 24 publications

(23 citation statements)

References 22 publications

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“…In addition, it is worth noting that Xa can inhibit DNA damage repair as a DNA damage inducer, which might account for the different cell cycle arrests under the treatment of Xa in NSCLC cells. Actually, similar results had also been previously reported 20 . Mechanistically, overproduction of DSBs can cause a strong cell cycle arrest at the G0/G1 phase, 45 while HR‐deficient cells are easily blocked at the G2/M phase because HR occurs between sister chromatids 12 .…”

Section: Discussionsupporting

confidence: 86%

“…This structural basis makes Xa possess a great potential for inducing DNA damage 26 . Previous investigations demonstrated that Xa exerts its anticancer effect by inducing DNA damage, reticulum stress, oxidative stress and so on 19‐21,27 . However, the effects of Xa on the transcriptome of cancer cells have not been reported.…”

Section: Discussionmentioning

confidence: 99%

“…Xa has a broad spectrum of biological activities. Recent studies indicated that Xa has significant antitumor effects on a number of malignancies including lung cancer, 19 hepatocellular carcinoma, 20 colon cancer 21 and glioma 22 . Xa triggers Chk1‐mediated DNA damage response in lung cancer cells 19 .…”

Section: Introductionmentioning

confidence: 99%

“…19 Furthermore, Xa induces endoplasmic reticulum (ER) stress, leading to activation of apoptosis in hepatoma cells. 20 Moreover, Xa activates ROS/XIAP signaling pathway to mediate G2/M cell cycle block and autophagy in colon cancer cells. 21 Nevertheless, the mechanisms of Xa's antitumor effects have not yet been defined.…”

mentioning

confidence: 99%

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Xanthatin synergizes with cisplatin to suppress homologous recombination through JAK2/STAT4/BARD1 axis in human NSCLC cells

Zhang

Yang

Guan

et al. 2021

J Cellular Molecular Medi

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Xanthatin (Xa) is a bicyclic sesquiterpene lactone identified from the plant Xanthium L . with impressive antitumor activity, but the role of Xa in non‐small cell lung cancer (NSCLC) is not known. Here we found that Xa inhibits proliferation, migration, invasion and induces apoptosis in NSCLC cells. RNA sequencing and Gene set enrichment analysis revealed that Xa significantly activates p53 pathway and suppresses E2F targets, G2M checkpoint and MYC targets in A549 cells. Among these changed genes, the down‐regulated gene BARD1 triggered by Xa was identified as a candidate involved in Xa’s antitumor effect because of its vital role in homologous recombination (HR). Further studies demonstrated that Xa inhibits HR through the BARD1/BRCA1/RAD51 axis, which enhances cell sensitivity to cisplatin. Mechanistic studies showed that Xa inhibits BARD1 through the JAK2/STAT4 pathway. Our study revealed that Xa is a promising drug to treat NSCLC, especially in combination with conventional chemotherapy.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Xanthatin synergizes with cisplatin to suppress homologous recombination through JAK2/STAT4/BARD1 axis in human NSCLC cells

Zhang

Yang

Guan

et al. 2021

J Cellular Molecular Medi

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“…Additionally, xanthatin induced apoptosis associated to activation of caspase-3. These effects were significantly abolished by siRNA-mediated knockdown of CHOP [50].…”

Section: Natural Compounds Targeting Er Stress-mediated Apoptosis: "Amentioning

confidence: 98%

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

Martucciello

Masullo

Cerulli

et al. 2020

IJMS

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The endoplasmic reticulum (ER) is a dynamic organelle essential for intracellular homeostasis maintenance, controlling synthesis, the folding of secreted and membrane-bound proteins, and transport of Ca2+. During cellular stress, ER dysfunction leads to the activation of unfolded protein response (UPR) due to accumulated misfolded proteins in the ER. This condition is referred as ER stress. Mitochondria and ER form a site of close contact (the mitochondria-associated membrane, MAM) which is a major platform exerting important physiological roles in the regulation of intracellular Ca2+ homeostasis, lipid metabolism, mitochondrial fission, autophagosome formation, and apoptosis progression. Natural products have been receiving increasing attention for their ability to interfere with ER stress. Research works have focused on the capacity of these bioactive compounds to induce apoptosis by activating ER stress through the ER stress-mediated mitochondrial apoptotic pathway. In this review we discuss the role of natural products in the signaling communication between ER and mitochondria, focusing on the effects induced by ER stress including Ca2+ permeability transition and UPR signaling (protein kinase R-like ER kinase/mitofusin 2).

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Xanthatin inhibits human colon cancer cells progression via mTOR signaling mediated energy metabolism alteration

Liu

Xie

et al. 2021

Drug Development Research

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Tumor cells exhibit higher glycolysis and rely on abnormal energy metabolism to produce ATP, which is essential for cell proliferation and migration. Abnormal energy metabolism inhibition is considered a promising tumor treatment strategy. Xanthatin is an active sesquiterpene lactone isolated from Xanthium strumarium L. This study evaluated the effect of xanthatin on the energy metabolism of human colon cancer cells. The results showed that xanthatin significantly inhibited the migration and invasion of human HT‐29 and HCT‐116 colon cancer cells. We found that xanthatin effectively reduced the production of ATP and promoted the accumulation of lactate. Xanthatin inhibited glycolysis which may be related to the reduction of glucose transporter 1 (Glut1) and monocarboxylate transporter 4 (MCT4) mRNA and protein levels. Concomitantly, xanthatin promoted complex II activity and oxidative phosphorylation (OXPHOS), resulting in mitochondrial damage and cell death in HT‐29 cells. Furthermore, xanthatin inhibited the phosphorylation of mTOR, the phosphorylation of 4E‐binding protein 1 (4E‐BP1) and c‐myc in HT‐29 cells. Moreover, rapamycin, a mTOR inhibitor, could enhance the cytotoxicity effect in xanthatin treated HT‐29 cells. Additionally, HT‐29 cells transfected with si‐mTOR aggravated xanthatin induced cell viability inhibition. Based on these results, we observed that the effect of xanthatin on energy metabolism may be related to its inhibition of the mTOR signaling pathway. Collectively, this study provides important insights into xanthatin's anticancer effect, which occurs by regulation of the energy metabolism of human colon cancer cells, and suggest that xanthatin has potential as a botanical drug against abnormal tumor energy metabolism.

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Xanthatin induces apoptosis by activating endoplasmic reticulum stress in hepatoma cells

Cited by 24 publications

References 22 publications

Xanthatin synergizes with cisplatin to suppress homologous recombination through JAK2/STAT4/BARD1 axis in human NSCLC cells

Xanthatin synergizes with cisplatin to suppress homologous recombination through JAK2/STAT4/BARD1 axis in human NSCLC cells

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

Xanthatin inhibits human colon cancer cells progression via mTOR signaling mediated energy metabolism alteration

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