Isochaihulactone-induced DDIT3 causes ER stress-PERK independent apoptosis in glioblastoma multiforme cells

Abstract

The endoplasmic reticulum (ER) is a major site of cellular homeostasis regulation. Under the ER stress condition, Glioblastoma multiform (GBM) cells activate the unfolded protein response. In this study, we discovered isochaihulactone, a natural compound extracted from the Chinese traditional herb Nan-Chai-Hu, which can disrupt ER homeostasis in GBM cell lines. It can induce DNA damage inducible transcript 3 (DDIT3) expression which is independent of 78 kDa glucose-regulated protein (GRP78) and protein kinase RNA-like endoplasmic reticulum kinase (PERK) expression. Flow cytometry results revealed that isochaihulactone trigger the cell cycle arrest at G2/M phase and apoptosis in GBM cells. Isochaihulactone induced DDIT3 led to the expression of NAG-1. The in vivo study showed that isochaihulactone suppressed tumor growth, and DDIT3 and Caspase3 overexpressed in the xenograft model, which is consistent with the in vitro study. Overall, the data revealed that isochaihulactone disrupted ER homeostasis in cancer cells by increasing DDIT3 and NAG-1 expression. Our finding also provides a therapeutic strategy by using isochaihulactone for GBM treatment.

Transcriptome Analysis of Circulating Immune Cell Subsets Highlight the Role of Monocytes in Zaire Ebola Virus Makona Pathogenesis

“…Upregulated genes that also enriched to “Immune system process” but not included in the network include: CD274 (PD-L1), which inhibits T-cell activation ( 47 ); neutrophil chemoattractant IL8 ( 48 ); and monocyte chemoattractant CCL8 (Monocyte chemotactic protein 2) ( 49 ). Notable upregulated genes that play a role in apoptosis and oxidative stress include DDIT3 (DNA Damage Inducible Transcript 3) ( 50 ), HSPB1 (Heat shock protein Family B Member 1) ( 51 ) CASP5 (Caspase 5) ( 52 ), and BIRC3 (Baculoviral IAP Repeat Containing 3) ( 53 ) (Figure 3 B).…”

Silencing of both ATF4 and PERK inhibits cell cycle progression and promotes the apoptosis of differentiating chondrocytes

“…PERK and ATF4 have been shown to play important roles in osteoblast differentiation and bone formation. Specifically, Saito et al as well as others revealed that ER stress occured during BMP2-induced osteoblast differentiation and activated the PERK-eIF2α-ATF4 signaling pathway, followed by the promotion of gene expression essential for osteogenesis ( 13 – 15 ). In an effort to disentangle the dual association of PERK/ATF4 signaling with both pro-survival and pro-apoptotic responses during ER stress, Walter et al , and others, investigated the association between cell fate and the temporal activation of PERK/ATF4 in live cells and found that the shift from cell survival to apoptosis was determined by the timing of PERK/ATF4 signaling relative to that of IRE1/XBP1, another UPR signaling pathway ( 16 , 17 ).…”

GDF‐15: Diagnostic, prognostic, and therapeutic significance in glioblastoma multiforme

“…K8‐induced GDF‐15 expression caused 8401 cell apoptosis (Tsai et al, 2017). 8401 and G2T cells have a high level of PERK, without DDIT3 expression (Tsai et al, 2017). K8 decreases the glioblastoma cell viability while being applied in tandem with GSK 2606414.…”