Glucose-Regulated Protein 78 Signaling Regulates Hypoxia-Induced Epithelial–Mesenchymal Transition in A549 Cells

Sun, Lingling; Chen, Chang-Ming; Zhang, Jue; Wang, Jing; Yang, Cai-Zhi; Lin, Lizhu

doi:10.3389/fonc.2019.00137

Cited by 19 publications

(17 citation statements)

References 30 publications

(27 reference statements)

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“…In our approach, we utilized hypoxia-exposed primary HUVECs from 10 pooled donors to determine the role of the ER stress on the HIF-1 signaling pathway. Despite the fact that previous studies reported the hypoxia-related induction of BIP expression [ 7 , 60 , 61 , 62 ], we found that BiP mRNA levels were reduced after a 12 h exposure to hypoxia. Furthermore, the significant accumulation of apoptotic CHOP ( DDIT3) mRNA was observed only in cells exposed to hypoxia for 24 h. Although CHOP accumulation and the potential induction of an apoptotic response were observed in some hypoxia experiments (including lung endothelial cells) [ 63 , 64 ], these protein and mRNA levels were much lower than those observed during ER stress [ 19 ].…”

Section: Discussioncontrasting

confidence: 99%

IRE1 Endoribonuclease Activity Modulates Hypoxic HIF-1α Signaling in Human Endothelial Cells

2020

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While the role of hypoxia and the induction of the hypoxia inducible factors (HIFs) and the unfolded protein response (UPR) pathways in the cancer microenvironment are well characterized, their roles and relationship in normal human endothelium are less clear. Here, we examined the effects of IRE1 on HIF-1α protein levels during hypoxia in primary human umbilical vein endothelial cells (HUVECs). The results demonstrated that HIF-1α levels peaked at 6 h of hypoxia along with two of their target genes, GLUT1 and VEGFA, whereas at up to 12 h of hypoxia the mRNA levels of markers of the UPR, IRE1, XBP1s, BiP, and CHOP, did not increase, suggesting that the UPR was not activated. Interestingly, the siRNA knockdown of IRE1 or inhibition of IRE1 endonuclease activity with 4µ8C during hypoxia significantly reduced HIF-1α protein without affecting HIF1A mRNA expression. The inhibition of the endonuclease activity with 4µ8C in two other primary endothelial cells during hypoxia, human cardiac microvascular endothelial cells and human aortic endothelial cells showed the same reduction in the HIF-1α protein. Surprisingly, the siRNA knockdown of XBP1s during hypoxia did not decrease the HIF1α protein levels, indicating that the IRE1-mediated effect on stabilizing the HIF1α protein levels was XBP1s-independent. The studies presented here, therefore, provide evidence that IRE1 activity during hypoxia increases the protein levels of HIF1α in an XBP1s-independent manner.

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Section: Discussioncontrasting

confidence: 99%

IRE1 Endoribonuclease Activity Modulates Hypoxic HIF-1α Signaling in Human Endothelial Cells

2020

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“…EMT markers were found to be correlated with increased GRP78 in samples from patients with lung adenocarcinoma [224]. Contrary to all those publications [214][215][216][217][218][219][220][221][222][223][224], there are at least three research papers dedicated to hepatocellular carcinoma cells [225][226][227] in which EMT and cancer stemness were associated with downregulation of intracellular GRP78, which seems rather unexpected and hard to explain. Such intriguing findings force the suggestion of some unusual activities of GRP78 in hepatocellular carcinomas.…”

Section: Intracellular Grp78mentioning

confidence: 88%

“…The enhanced expression of GRP78, Src, MAPK, and Smad2/3 seemed to be associated with hypoxia-induced EMT in lung cancer A549 cells [218]. More recent investigations on the same model have revealed the role of intracellular GRP78 as the key endogenous regulator of EMT in hypoxia-stressed A549 cells: Hypoxia upregulates the expression of GRP78 while increased GRP78, in turn, mediates the activating phosphorylation of Smad2/3, Src, p38, ERK, and JNK, thus promoting EMT via activation of the Smad2/3 and Src/MAPK signaling pathways [219]. In a model of non-small lung cancer, the GRP78-dependent mechanism of EMT was realized via the PI3K/Akt/Mdm2 signaling pathway, which was sensitive to GRP78 downregulation by the differentially expressed in adenocarcinoma of the lung (DAL-1) [217].…”

Section: Intracellular Grp78mentioning

confidence: 94%

“…Many publications confirm the role of intracellular GRP78 as one of the EMT regulators in various human carcinomas [214][215][216][217][218][219][220][221][222][223][224]. It was shown that GRP78 promotes EMT in head and neck cancer cells [214], colon cancer cells [215], lung cancer cells [216][217][218][219], breast cancer cells [220,221], nasopharyngeal carcinoma cells [222], prostate cancer, and multiple myeloma cells [223]. EMT markers were found to be correlated with increased GRP78 in samples from patients with lung adenocarcinoma [224].…”

Section: Intracellular Grp78mentioning

confidence: 99%

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Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Kabakov

Yakimova

Matchuk

2020

Cells

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Cancer stem cells (CSCs) are a great challenge in the fight against cancer because these self-renewing tumorigenic cell fractions are thought to be responsible for metastasis dissemination and cases of tumor recurrence. In comparison with non-stem cancer cells, CSCs are known to be more resistant to chemotherapy, radiotherapy, and immunotherapy. Elucidation of mechanisms and factors that promote the emergence and existence of CSCs and their high resistance to cytotoxic treatments would help to develop effective CSC-targeting therapeutics. The present review is dedicated to the implication of molecular chaperones (protein regulators of polypeptide chain folding) in both the formation/maintenance of the CSC phenotype and cytoprotective machinery allowing CSCs to survive after drug or radiation exposure and evade immune attack. The major cellular chaperones, namely heat shock proteins (HSP90, HSP70, HSP40, HSP27), glucose-regulated proteins (GRP94, GRP78, GRP75), tumor necrosis factor receptor-associated protein 1 (TRAP1), peptidyl-prolyl isomerases, protein disulfide isomerases, calreticulin, and also a transcription heat shock factor 1 (HSF1) initiating HSP gene expression are here considered as determinants of the cancer cell stemness and potential targets for a therapeutic attack on CSCs. Various approaches and agents are discussed that may be used for inhibiting the chaperone-dependent development/manifestations of cancer cell stemness.

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“…Notably, in addition to driving drug resistance, GRP78 has been shown to promote the stemness [ 55 , 56 ] and EMT [ 57 , 58 ] of cancer cells. In agreement, our HCC827GR-resistant subline possessing an elevated GRP78 level has also raised stemness and EMT markers, such as has been reported in published research [ 5 , 38 ].…”

Section: Discussionmentioning

confidence: 99%

Omega-3 Fatty Acid-Enriched Fish Oil and Selenium Combination Modulates Endoplasmic Reticulum Stress Response Elements and Reverses Acquired Gefitinib Resistance in HCC827 Lung Adenocarcinoma Cells

et al. 2020

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Non-small cell lung cancer (NSCLC)-carrying specific epidermal growth factor receptor (EGFR) mutations can be effectively treated by a tyrosine kinase inhibitor such as gefitinib. However, the inevitable development of acquired resistance leads to the eventual failure of therapy. In this study, we show the combination effect of omega-3 fatty acid-enriched fish oil (FO) and selenium (Se) on reversing the acquired gefitinib-resistance of HCC827 NSCLC cells. The gefitinib-resistant subline HCC827GR possesses lowered proapoptotic CHOP (CCAAT/enhancer-binding protein homologous protein) and elevated cytoprotective GRP78 (glucose regulated protein of a 78 kDa molecular weight) endoplasmic reticulum (ER) stress response elements, and it has elevated β-catenin and cyclooxygenase-2 (COX-2) levels. Combining FO and Se counteracts the above features of HCC827GR cells, accompanied by the suppression of their raised epithelial-to-mesenchymal transition (EMT) and cancer stem markers, such as vimentin, AXL, N-cadherin, CD133, CD44, and ABCG2. Accordingly, an FO and Se combination augments the gefitinib-mediated growth inhibition and apoptosis of HCC827GR cells, along with the enhanced activation of caspase -3, -9, and ER stress-related caspase-4. Intriguingly, gefitinib further increases the elevated ABCG2 and cancer stem-like side population in HCC827GR cells, which can also be diminished by the FO and Se combination. The results suggest the potential of combining FO and Se in relieving the acquired resistance of NSCLC patients to targeted therapy.

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Glucose-Regulated Protein 78 Signaling Regulates Hypoxia-Induced Epithelial–Mesenchymal Transition in A549 Cells

Cited by 19 publications

References 30 publications

IRE1 Endoribonuclease Activity Modulates Hypoxic HIF-1α Signaling in Human Endothelial Cells

IRE1 Endoribonuclease Activity Modulates Hypoxic HIF-1α Signaling in Human Endothelial Cells

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Omega-3 Fatty Acid-Enriched Fish Oil and Selenium Combination Modulates Endoplasmic Reticulum Stress Response Elements and Reverses Acquired Gefitinib Resistance in HCC827 Lung Adenocarcinoma Cells

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