Deficiency of protein-L-isoaspartate (D-aspartate) O-methyl-transferase expression under endoplasmic reticulum stress promotes epithelial mesenchymal transition in lung adenocarcinoma

Abstract

A prognostic association between the novel chaperone protein-L-isoaspartate (D-aspartate) O-methyltransferase (PIMT) and lung adenocarcinoma has recently been reported. Here, we evaluated the functional roles of PIMT in the progression of lung adenocarcinoma. PIMT expression was detectable in 6 lung adenocarcinoma cell lines: A549, H441, H460, H1650, Calu 1, and Calu 6 cell lines. In A549 and H441 cells, knockdown by PIMT using silencing RNA of PIMT (si-PIMT) and/or small hairpin-RNA (sh-PIMT) induced a decrease in the expression of E-cadherin with an increase in vimentin expression, indicating that the epithelial to mesenchymal transition (EMT) was induced. Cell mobility, including migration and invasion capability, was increased in sh-PIMT A549 stable and si-PIMT H441 cells compared to in control cells. Endoplasmic reticulum (ER) stress, such as Thapsigargin (Tg) stress and hypoxia, induced EMT in A549 cells but not in other cell types, with an increase in GRP78 expression, whereas overexpression of PIMT reduced the EMT and cell invasion under stress conditions. The expression of hypoxia inducible factor-1 alpha (HIF1α) and Twist increased in sh-PIMT A549 and si-PIMT H441 cells, and Tg stress increased HIF1α expression levels in A549 cells in a dose-dependent manner. Moreover, LW6, an HIF1α inhibitor, reduced EMT, cancer invasion, and the levels of Twist in sh-PIMT A549 cells. Our results indicate that deficiency of supplemental PIMT expression under ER stress facilitates EMT and cell invasion in some cell types of lung adenocarcinoma.

Hydroxypropyl‑β‑cyclodextrin attenuates the epithelial‑to‑mesenchymal transition via endoplasmic reticulum stress in MDA‑MB‑231 breast cancer cells

“…The role of ER stress in EMT is somewhat controversial. Huang et al (21) demonstrated that pterostilbene-induced ER stress could inhibit EMT in breast cancer, and recent studies have pointed to a relationship between the TGF-β/Smad signaling pathway and ER stress in a number of cell lines, including A549 cells and podocytes (19,38) suggesting that TGF-β1 can activate ER stress to promote the process of EMT. The present study demonstrated that HP-β-CD could block both the TGF-β/Smad signaling pathway and EMT, revealing a positive association between TGF-β/Smad signaling pathway and EMT, in line with the studies of Moon et al (38) and Yamashita et al (19).…”

“…Huang et al (21) demonstrated that pterostilbene-induced ER stress could inhibit EMT in breast cancer, and recent studies have pointed to a relationship between the TGF-β/Smad signaling pathway and ER stress in a number of cell lines, including A549 cells and podocytes (19,38) suggesting that TGF-β1 can activate ER stress to promote the process of EMT. The present study demonstrated that HP-β-CD could block both the TGF-β/Smad signaling pathway and EMT, revealing a positive association between TGF-β/Smad signaling pathway and EMT, in line with the studies of Moon et al (38) and Yamashita et al (19). However, in contrast to these reports, the present study found that HP-β-CD could induce ER stress to attenuate the EMT, indicating a negative association, and this is in line with Huang et al (21) and Dasgupta et al (39) who found that pterostilbene and AECHL-1 suppressed the EMT by activating ER stress in breast cancer.…”

“…When the integrity of the ER is disturbed by adverse conditions, misfolded proteins will accumulate in the ER, giving rise to misfolded protein response, or ER stress, which is associated with many cellular biological functions, including EMT (17,18). In addition, a definite association has demonstrated that the TGF-β/Smad signaling pathway can regulate ER stress in lung cancer cells (19), podocytes (20) and even breast cancer cells (21). Therefore, it was hypothesized that HP-β-CD could regulate ER stress via TGF-β/Smad signaling pathway to influence EMT in MDA-MB-231 cells.…”

The Protein L-Isoaspartyl (D-Aspartyl) Methyltransferase Regulates Glial-to-Mesenchymal Transition and Migration Induced by TGF-β1 in Human U-87 MG Glioma Cells

“…Previously, we demonstrated that PIMT isoform 1 could regulate oncogenic features such as migration, invasion, and adhesion in U-87 MG glioma cells, and that this isoform was able to modulate cell morphology by remodelling F-actin and microtubule polymerization [ 10 ]. Other studies have reported that PIMT could regulate the expression of EMT markers in MDA-MB-231 breast cancer cells [ 7 ], in BUI-87 and SW780 bladder cancer cells [ 19 ], and in different lung adenocarcinoma cell lines [ 20 ]. Thus, these observations led us to investigate whether PIMT could be involved in EMT processes dependent on TGF-β1 when U-87 MG cells were treated with this cytokine.…”

Influence of D-asparagine on the proliferative activity of human dermal fibroblasts

“…D-аспартат, накапливающийся в составе белков при длительной инкубации, может оказывать негативное влияние на их функциональную активность. Это подтверждается тем, что функционирование L-изоаспартат DL-аспартат О-метилтрансферазы (конвертирует D-аспартат в L-форму) является критичным для нормального деления и дифференцировки клеток [10].…”