Dataset Information

Z-Ligustilide Induces c-Myc-Dependent Apoptosis via Activation of ER-Stress Signaling in Hypoxic Oral Cancer Cells.

ABSTRACT: Z-ligustilide (or ligustilide) is found in Angelica sinensis (Oliv.) Diels and may exert potential benefits in cancer treatment. Previous research has reported that ligustilide has anti-cancer effects on several types of cancer cells. However, studies of ligustilide on oral cancer cells have not been reported, especially under hypoxic conditions. This study focuses on the molecular mechanism of ligustilide-induced apoptosis in hypoxic oral cancer cells. We found that in hypoxic TW2.6 cells, ligustilide inhibited cell migration and induced caspase-dependent apoptosis. Accumulation of c-Myc accompanied by BH3-only members suggests that ligustilide may induce c-Myc-dependent apoptosis. In addition, we reported that ligustilide has an effect on ER-stress signaling. By using inhibitors of c-Myc, IRE1α, and ER-stress inhibitors, we found that cell morphologies or cell viability were rescued to some degree. Moreover, ligustilide is able to increase the expression of γ-H2AX and enhance the occurrence of DNA damage in oral cancer cells after radiation treatment. This result suggests that ligustilide has potential as a radiation sensitizer. Altogether, we propose that ligustilide may induce c-Myc-dependent apoptosis via ER-stress signaling in hypoxic oral cancer cells.

SUBMITTER: Hsu RJ

PROVIDER: S-EPMC9043595 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Z-Ligustilide Induces c-Myc-Dependent Apoptosis via Activation of ER-Stress Signaling in Hypoxic Oral Cancer Cells.

Hsu Ren-Jun RJ Peng Kui-Yuan KY Hsu Wen-Lin WL Chen Yu-Tang YT Liu Dai-Wei DW

Frontiers in oncology 20220413

Z-ligustilide (or ligustilide) is found in Angelica sinensis (Oliv.) Diels and may exert potential benefits in cancer treatment. Previous research has reported that ligustilide has anti-cancer effects on several types of cancer cells. However, studies of ligustilide on oral cancer cells have not been reported, especially under hypoxic conditions. This study focuses on the molecular mechanism of ligustilide-induced apoptosis in hypoxic oral cancer cells. We found that in hypo ...[more]

PMID: 35494068

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Project description:The incidence of chronic liver disease is constantly increasing, owing to the obesity epidemic. However, the causes and mechanisms of inflammation-mediated liver damage remain poorly understood. Endoplasmic reticulum (ER) stress is an initiator of cell death and inflammatory mechanisms. Although obesity induces ER stress, the interplay between hepatic ER stress, NLRP3 inflammasome activation and hepatocyte death signaling has not yet been explored during the etiology of chronic liver diseases. Steatosis is a common disorder affecting obese patients; moreover, 25% of these patients develop steatohepatitis with an inherent risk for progression to hepatocarcinoma. Increased plasma LPS levels have been detected in the serum of patients with steatohepatitis. We hypothesized that, as a consequence of increased plasma LPS, ER stress could be induced and lead to NLRP3 inflammasome activation and hepatocyte death associated with steatohepatitis progression. In livers from obese mice, administration of LPS or tunicamycin results in IRE1α and PERK activation, leading to the overexpression of CHOP. This, in turn, activates the NLRP3 inflammasome, subsequently initiating hepatocyte pyroptosis (caspase-1, -11, interleukin-1β secretion) and apoptosis (caspase-3, BH3-only proteins). In contrast, the LPS challenge is blocked by the ER stress inhibitor TUDCA, resulting in: CHOP downregulation, reduced caspase-1, caspase-11, caspase-3 activities, lowered interleukin-1β secretion and rescue from cell death. The central role of CHOP in mediating the activation of proinflammatory caspases and cell death was characterized by performing knockdown experiments in primary mouse hepatocytes. Finally, the analysis of human steatohepatitis liver biopsies showed a correlation between the upregulation of inflammasome and ER stress markers, as well as liver injury. We demonstrate here that ER stress leads to hepatic NLRP3 inflammasome pyroptotic death, thus contributing as a novel mechanism of inflammation-mediated liver injury in chronic liver diseases. Inhibition of ER-dependent inflammasome activation and cell death pathways may represent a potential therapeutic approach in chronic liver diseases.

Dataset Information

Z-Ligustilide Induces c-Myc-Dependent Apoptosis via Activation of ER-Stress Signaling in Hypoxic Oral Cancer Cells.

Publications

Z-Ligustilide Induces c-Myc-Dependent Apoptosis <i>via</i> Activation of ER-Stress Signaling in Hypoxic Oral Cancer Cells.

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