scholarly journals Triptolide activates unfolded protein response leading to chronic ER stress in pancreatic cancer cells

2014 ◽  
Vol 306 (11) ◽  
pp. G1011-G1020 ◽  
Author(s):  
Nameeta Mujumdar ◽  
Sulagna Banerjee ◽  
Zhiyu Chen ◽  
Veena Sangwan ◽  
Rohit Chugh ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Death ◽  
Stress Response ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Initiation Factor ◽  
Unfolded Protein ◽  
Pancreatic Cancer Cells ◽  
Cancer Aggressiveness ◽  
Protein Response

Pancreatic cancer is a devastating disease with a survival rate of <5%. Moreover, pancreatic cancer aggressiveness is closely related to high levels of prosurvival mediators, which can ultimately lead to rapid disease progression. One of the mechanisms that enables tumor cells to evade cellular stress and promote unhindered proliferation is the endoplasmic reticulum (ER) stress response. Disturbances in the normal functions of the ER lead to an evolutionarily conserved cell stress response, the unfolded protein response (UPR). The UPR initially compensates for damage, but it eventually triggers cell death if ER dysfunction is severe or prolonged. Triptolide, a diterpene triepoxide, has been shown to be an effective compound against pancreatic cancer. Our results show that triptolide induces the UPR by activating the PKR-like ER kinase-eukaryotic initiation factor 2α axis and the inositol-requiring enzyme 1α-X-box-binding protein 1 axis of the UPR and leads to chronic ER stress in pancreatic cancer. Our results further show that glucose-regulated protein 78 (GRP78), one of the major regulators of ER stress, is downregulated by triptolide, leading to cell death by apoptosis in MIA PaCa-2 cells and autophagy in S2-VP10 cells.

scholarly journals HY5, a positive regulator of light signaling, negatively controls the unfolded protein response inArabidopsis

2017 ◽  
Vol 114 (8) ◽  
pp. 2084-2089 ◽  
Author(s):  
Ganesh M. Nawkar ◽  
Chang Ho Kang ◽  
Punyakishore Maibam ◽  
Joung Hun Park ◽  
Young Jun Jung ◽  
...  
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Molecular Mechanism ◽  
26S Proteasome ◽  
Light Signaling ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
The Unfolded Protein Response ◽  
Protein Response

Light influences essentially all aspects of plant growth and development. Integration of light signaling with different stress response results in improvement of plant survival rates in ever changing environmental conditions. Diverse environmental stresses affect the protein-folding capacity of the endoplasmic reticulum (ER), thus evoking ER stress in plants. Consequently, the unfolded protein response (UPR), in which a set of molecular chaperones is expressed, is initiated in the ER to alleviate this stress. Although its underlying molecular mechanism remains unknown, light is believed to be required for the ER stress response. In this study, we demonstrate that increasing light intensity elevates the ER stress sensitivity of plants. Moreover, mutation of the ELONGATED HYPOCOTYL 5 (HY5), a key component of light signaling, leads to tolerance to ER stress. This enhanced tolerance ofhy5plants can be attributed to higher expression of UPR genes. HY5 negatively regulates the UPR by competing with basic leucine zipper 28 (bZIP28) to bind to the G-box–like element present in the ER stress response element (ERSE). Furthermore, we found that HY5 undergoes 26S proteasome-mediated degradation under ER stress conditions. Conclusively, we propose a molecular mechanism of crosstalk between the UPR and light signaling, mediated by HY5, which positively mediates light signaling, but negatively regulates UPR gene expression.

scholarly journals Human Cytomegalovirus Protein pUL38 Induces ATF4 Expression, Inhibits Persistent JNK Phosphorylation, and Suppresses Endoplasmic Reticulum Stress-Induced Cell Death

2009 ◽  
Vol 83 (8) ◽  
pp. 3463-3474 ◽  
Author(s):  
Baoqin Xuan ◽  
Zhikang Qian ◽  
Emi Torigoi ◽  
Dong Yu
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Human Cytomegalovirus ◽  
Initiation Factor ◽  
Α Subunit ◽  
Unfolded Protein ◽  
Initiation Factor 2 ◽  
The Unfolded Protein Response ◽  
Protein Response

ABSTRACT The endoplasmic reticulum (ER) is a key organelle involved in sensing and responding to stressful conditions, including those resulting from infection of viruses, such as human cytomegalovirus (HCMV). Three signaling pathways collectively termed the unfolded protein response (UPR) are activated to resolve ER stress, but they will also lead to cell death if the stress cannot be alleviated. HCMV is able to modulate the UPR to promote its infection. The specific viral factors involved in such HCMV-mediated modulation, however, were unknown. We previously showed that HCMV protein pUL38 was required to maintain the viability of infected cells, and it blocked cell death induced by thapsigargin. Here, we report that pUL38 is an HCMV-encoded regulator to modulate the UPR. In infection, pUL38 allowed HCMV to upregulate phosphorylation of PKR-like ER kinase (PERK) and the α subunit of eukaryotic initiation factor 2 (eIF-2α), as well as induce robust accumulation of activating transcriptional factor 4 (ATF4), key components of the PERK pathway. pUL38 also allowed the virus to suppress persistent phosphorylation of c-Jun N-terminal kinase (JNK), which was induced by the inositol-requiring enzyme 1 pathway. In isolation, pUL38 overexpression elevated eIF-2α phosphorylation, induced ATF4 accumulation, limited JNK phosphorylation, and suppressed cell death induced by both thapsigargin and tunicamycin, two drugs that induce ER stress by different mechanisms. Importantly, ATF4 overexpression and JNK inhibition significantly reduced cell death in pUL38-deficient virus infection. Thus, pUL38 targets ATF4 expression and JNK activation, and this activity appears to be critical for protecting cells from ER stress induced by HCMV infection.

scholarly journals NUCB1 Suppresses Growth and Shows Additive Effects With Gemcitabine in Pancreatic Ductal Adenocarcinoma via the Unfolded Protein Response

2021 ◽  
Vol 9 ◽  
Author(s):  
Yong-Qiang Hua ◽  
Ke Zhang ◽  
Jie Sheng ◽  
Zhou-Yu Ning ◽  
Ye Li ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Unfolded Protein Response ◽  
Calcium Binding ◽  
Ductal Adenocarcinoma ◽  
Additive Effects ◽  
Unfolded Protein ◽  
Pancreatic Cancer Cells ◽  
The Unfolded Protein Response ◽  
Protein Response

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor patient prognosis. A cellular stress response mechanism called the unfolded protein response (UPR) has been implicated in PDAC progression. More recently, nucleobindin 1 (NUCB1), a calcium-binding protein, has been shown to control the UPR but its precise role in PDAC has not been explored. Here, we found that downregulation of NUCB1 was associated with poor prognosis in patients with PDAC. Functionally, NUCB1 overexpression suppressed pancreatic cancer cell proliferation and showed additive effects with gemcitabine (GEM) in vitro and in vivo. Moreover, by controlling ATF6 activity, NUCB1 overexpression suppressed GEM-induced UPR and autophagy. Last but not least, we uncovered METTL3-mediated m6A modification on NUCB1 5′UTR via the reader YTHDF2 as a mechanism for NUCB1 downregulation in PDAC. Taken together, our study revealed crucial functions of NUCB1 in suppressing proliferation and enhancing the effects of gemcitabine in pancreatic cancer cells and identified METTL3-mediated m6A modification as a mechanism for NUCB1 downregulation in PDAC.

Abstract 1313: Pro-atherogenic Effects Of Lipid Peroxidation Products: Role Of The Unfolded Protein Response

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Elena Vladykoskaya ◽  
Petra Haberzettl ◽  
Yonis Ahmed ◽  
Bradford G Hill ◽  
Srinivas D Sithu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Initiation Factor ◽  
Chemical Chaperone ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Jnk Activation

Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are associated with atherosclerosis. Expression of UPR target genes such as activating transcription factor 3 (ATF3) and ATF4 is markedly increased in human atherosclerotic lesions. Staining for these proteins co-localizes with the staining with antibodies that recognize the aldehydic epitopes of oxidized LDL, suggesting that lipid-derived aldehydes could be involved in mediating ER stress and UPR. We examined the role of phospholipid aldehyde, 1-palmitoyl-2-(5-oxovaleroyl)- sn -glycero-3-phosphocholine (POVPC), unsaturated lipid-derived aldehydes- 4-hydroxy, trans -2-nonenal (HNE) and acrolein in the induction of ER-stress and UPR in human aortic endothelial cells (HAEC) and human umbical vein endothelial cells (HUVEC). POVPC, HNE and acrolein (10 –25 μM) increased the phosphorylation of eIF2α (eukaryotic initiation factor-2α) by 1.5–5 fold (P<0.001) and induced its downstream effector proteins - ATF4 (1.5–3.5 fold; P<0.001) and ATF3 (4–10 fold; P<0.0001). Incubation of HAEC with these aldehydes also increased the adhesion of THP-1 cells (monocyte) to HAEC by 1.4–1.6 fold (P<0.01). Moreover, incubation of endothelial cells with POVPC increased the mRNA level of the pro-inflammatory cytokine IL-8 by >25 fold (P<0.0001). Chemical chaperone, phenyl butyric acid (PBA), diminished aldehydes-induced expression of ATF3 and ATF4 proteins, endothelial cell-monocyte adhesion and IL-8 formation by 80–95% (P<0.001). POVPC (10–25 μM) also activated JNK by (3–6 fold) in HAEC. Reduction of POVPC to its corresponding alcohol, 1-palmitoyl-2-(5-hydroxyvaleroyl)- sn -glycero-3-phosphocholine (PHVPC) inhibited JNK activation by 74 ± 14 % (P<0.001). Pharmacological inhibition of JNK, inhibited the aldehyde-induced induction of ATF3 and ATF4 proteins by 70–90 % (P<0.001) but not the phosphorylation of eIF2α, and PBA inhibited the POVPC-induced JNK activation by 85 ± 11 % (P<0.001). These data suggest that lipoprotein oxidation products activate endothelial cells in part by inducing ER-stress and their inflammatory signaling could be attenuated by chemical chaperones of protein folding.

Modulation of ER Stress/Unfolded Protein Response (UPR) Pathways in Multiple Myeloma Cells by Inhibition of Hsp90 and Serine-Threonine Kinase CK2.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3840-3840
Author(s):  
Francesco Piazza ◽  
Sabrina Manni ◽  
Carmela Gurrieri ◽  
Anna Colpo ◽  
Laura Quotti Tubi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Death ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Hsp90 Inhibitors ◽  
Hsp90 Inhibition ◽  
Protein Levels ◽  
Unfolded Protein ◽  
Protein Response ◽  
Kinase Ck2

Abstract Abstract 3840 Poster Board III-776 Hsp90 is an essential chaperone molecule that helps in the maturation and folding of a number of cellular client proteins. Hsp90 function is essential for malignant plasma cell survival, since its inhibition in multiple myeloma (MM) cells results in cell death and activation of apoptosis. Clinical trials using Hsp90 inhibitors are currently ongoing in MM patients. Hsp90 inactivation in MM cells causes perturbation of the endoplasmic reticulum (ER) stress/unfolded protein response (UPR), eventually triggering the apoptotic cascades. Protein kinase CK2 critically regulates the activity of the chaperone complex formed by the Cdc37 and Hsp90 proteins. We already described that CK2 is over-expressed in a fraction of MM patients and is an essential MM pro-survival molecule. We have here investigated its role in the ER stress/UPR pathways and in Hsp90 inhibition-induced apoptosis in MM cells. Down-regulation of the catalytic CK2 alpha subunit with selective chemical inhibitors or RNA interference resulted in significant modifications of the main UPR regulating signaling cascades: 1) a marked reduction of IRE1alpha protein levels; 2) a reduction of BiP/GRP78 and Hsp70 chaperone protein levels; 3) an increase of PERK activity and phospho eIF2alpha levels. When UPR was triggered by thapsigargin in CK2-inactivated cells, we observed that the IRE1alpha-dependent axis of the UPR was greatly impaired, as XBP-1short isoform generation and the levels of some induced chaperones were reduced. Interestingly, thapsigargin was able to induce CK2 kinase activity. Remarkably, treatment of CK2-silenced MM cells with Hsp90 inhibitors geldanamycin or its derivative 17-AAG (17-(demethoxy)-17-allylamino geldanamycin) resulted in 1) an even more pronounced reduction of IRE1 alpha protein levels; 2) a marked inhibition of GA or 17-AAG-triggered BiP/GRP78 protein level raise; 3) a more evident increase of eIF2 alpha phosphorylation. Of note, CK2 plus Hsp90 inhibition was followed by apoptotic cell death to a much greater extent than that obtained with the single inhibition of the two molecules. Noteworthy, these effects were also reproduced upon modelling the MM bone marrow (BM) microenvironment by co-culturing MM cells with BM stromal cells. These data suggest that CK2-mediated signaling regulates the ER stress/UPR pathways and modulates the threshold to apoptosis of ER stressed MM cells. CK2 interacts with Hsp90, since its inhibition synergizes with GA or 17-AAG treatments in terms of induction of apoptosis and shift of the ER stress/UPR pathways towards the terminal phase. These results might be useful to set the groundwork in designing novel combination treatments for MM patients. Disclosures: No relevant conflicts of interest to declare.

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