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.
Highlights
Lung cancer is a major global health concern, and non–small cell lung cancer is the most common disease type [1]
We explored the expression of protein-L-isoaspartate (D-aspartate) O-methyltransferase (PIMT) in 6 lung adenocarcinoma cells lines: A549, H441, H460, H1650, Calu 1, and Calu 6 cells (Figure 1A and 1B)
GRP78 expression was detected in H460 cells, but weakly expressed in the remaining lineages. p53 expression was remarkably decreased in H1650, Calu 1, and Calu 6 cells, while expression was detected in A549, H441, and H460 cells
Summary
Lung cancer is a major global health concern, and non–small cell lung cancer is the most common disease type [1]. Carcinogenesis, tumorigenesis, invasion, and distant metastasis of cancer cells are involved in cancer development [3, 4]. Various stresses, such as oxidant stress, malnutrition, and hypoxia within tissue, are exerted on cancer cells through these processes and can cause the accumulation of unfolded proteins in the ER [5,6,7]. Molecular chaperones can fold various types of unfolded proteins induced by ER stress. A large number of studies has shown that molecular chaperones show increased expressed in cancer cells, and it has been speculated that molecular chaperones facilitate the survival of cancer cells via anti-apoptotic effects [8, 9]
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