scholarly journals Induction of Endoplasmic Reticulum-induced Stress Genes in Panc-1 Pancreatic Cancer Cells Is Dependent on Sp Proteins

2005 ◽  
Vol 280 (16) ◽  
pp. 16508-16513 ◽  
Author(s):  
Maen Abdelrahim ◽  
Shengxi Liu ◽  
Stephen Safe
Keyword(s):  
Pancreatic Cancer ◽  
Endoplasmic Reticulum ◽  
Transcription Factors ◽  
Stress Response ◽  
Er Stress ◽  
Cancer Cells ◽  
Gene Promoters ◽  
Er Stress Response ◽  
Pancreatic Cancer Cells ◽  
Pharmacologically Active

Endoplasmic reticulum (ER) stress plays a critical role in multiple diseases, and pharmacologically active drugs can induce cell death through ER stress pathways. Stress-induced genes are activated through assembly of transcription factors on ER stress response elements (ERSEs) in target gene promoters. Gel mobility shift and chromatin immunoprecipitation assays have confirmed interactions of NF-Y and YY1 with the distal motifs of the tripartite ERSE from the glucose-related protein 78 (GRP78) gene promoter. The GC-rich nonanucleotide (N9) sequence, which forms the ER stress response binding factor (ERSF) complex binds TFII-I and ATF6; however, we have now shown that in Panc-1 pancreatic cancer cells, this complex also binds Sp1, Sp3, and Sp4 proteins. Sp proteins are constitutively bound to the ERSE; however, activation of GRP78 protein (or reporter gene) by thapsigargin or tunicamycin is inhibited after cotransfection with small inhibitory RNAs for Sp1, Sp3, and Sp4. This study demonstrates that Sp transcription factors are important for stress-induced responses through their binding to ERSEs.

scholarly journals Endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases

2017 ◽  
Author(s):  
Arnaud Pommier ◽  
Naishitha Anaparthy ◽  
Nicoletta Memos ◽  
Z Larkin Kelley ◽  
Alizée Gouronnec ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Cancer Cells ◽  
Ductal Adenocarcinoma ◽  
Cytokeratin 19 ◽  
Chemical Chaperone ◽  
Er Stress Response ◽  
Cancer Metastases

AbstractPatients who have had their primary pancreatic ductal adenocarcinoma (PDA) surgically resected often develop metastatic disease, exemplifying the problem of latent metastases. Livers from patients and mice with PDA contained single, disseminated cancer cells (DCCs) with an unusual phenotype of being cytokeratin-19 (CK19)- and MHC class I (MHCI)-. We created a mouse model to determine how DCCs develop, their relationship to metastatic latency, and the role of immunity. Intra-portal injection of immunogenic PDA cells into pre-immunized mice seeded livers only with single, non-replicating DCCs lacking MHCI and CK19; naïve recipients had macro-metastases. Transcriptomic analysis of PDA cells with the DCC phenotype demonstrated an endoplasmic reticulum (ER) stress response. Relieving ER stress with a chemical chaperone, in combination with T cell-depletion, stimulated outgrowth of macro-metastatic lesions containing PDA cells expressing MHCI and CK19. The ER stress response is the cell-autonomous reaction that enables DCCs to escape immunity and establish latent metastases.One sentence summary:Latent pancreatic cancer metastases are created when T cells select disseminated cancer cells in which immune resistance and quiescence have been imposed by endoplasmic stress.

scholarly journals Inactivation of NUPR1 promotes cell death by coupling ER-stress responses with necrosis

2018 ◽  
Author(s):  
Patricia Santofimia-Castaño ◽  
Wenjun Lan ◽  
Jennifer Bintz ◽  
Odile Gayet ◽  
Alice Carrier ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Death ◽  
Stress Response ◽  
Er Stress ◽  
Cancer Cells ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
Atp Production ◽  
Er Stress Response ◽  
Pancreatic Cancer Cells

AbstractGenetic inhibition of NUPR1 induces tumor growth arrest. Inactivation of NUPR1 expression in pancreatic cancer cells results in lower ATP production, higher consumption of glucose with a significant switch from OXPHOS to glycolysis followed by necrotic cell death. Importantly, induction of necrosis is independent of the caspase activity. We demonstrated that NUPR1 inactivation triggers a massive release of Ca2+from the endoplasmic reticulum (ER) to the cytosol and a strong increase in ROS production by mitochondria with a concomitant relocalization of mitochondria to the vicinity of the ER. In addition, transcriptomic analysis of NUPR1-deficient cells shows the induction of an ER stress which is associated to a decrease in the expression of some ER stress response-associated genes. Indeed, during ER stress induced by the treatment with thapsigargin, brefeldin A or tunicamycin, an increase in the mitochondrial malfunction with higher induction of necrosis was observed in NUPR1-defficent cells. Finally, activation of NUPR1 during acute pancreatitis protects acinar cells of necrosis in mice. Altogether, these data enable us to describe a model in which inactivation of NUPR1 in pancreatic cancer cells results in an ER stress that induces a mitochondrial malfunction, a deficient ATP production and, as consequence, the cell death by necrosis.HighlightsNUPR1 expression promotes pancreatic cancer development and progressionNUPR1-depletion is a promising therapeutic strategy to be used for treating cancersNUPR1-depletion induces ER stress, mitochondrial malfunction and a significant switch from OXPHOS to glycolysis followed by necrotic cell deathInactivation of NUPR1 antagonizes cell growth by coupling a defective ER-stress response and a caspase-independent necrosis.

scholarly journals Imexon Induces an Oxidative Endoplasmic Reticulum Stress Response in Pancreatic Cancer Cells

2012 ◽  
Vol 10 (3) ◽  
pp. 392-400 ◽  
Author(s):  
Elena V. Sheveleva ◽  
Terry H. Landowski ◽  
Betty K. Samulitis ◽  
Geoffrey Bartholomeusz ◽  
Garth Powis ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Endoplasmic Reticulum Stress ◽  
Cancer Cells ◽  
Endoplasmic Reticulum Stress Response ◽  
Pancreatic Cancer Cells

scholarly journals Direct Endoplasmic Reticulum Targeting by the Selective Alkylphospholipid Analog and Antitumor Ether Lipid Edelfosine as a Therapeutic Approach in Pancreatic Cancer

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4173
Author(s):  
Faustino Mollinedo ◽  
Consuelo Gajate
Keyword(s):  
Pancreatic Cancer ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Apoptotic Cell ◽  
Ether Lipid ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, shows a dismal and grim overall prognosis and survival rate, which have remained virtually unchanged for over half a century. PDAC is the most lethal of all cancers, with the highest mortality-to-incidence ratio. PDAC responds poorly to current therapies and remains an incurable malignancy. Therefore, novel therapeutic targets and drugs are urgently needed for pancreatic cancer treatment. Selective induction of apoptosis in cancer cells is an appealing approach in cancer therapy. Apoptotic cell death is highly regulated by different signaling routes that involve a variety of subcellular organelles. Endoplasmic reticulum (ER) stress acts as a double-edged sword at the interface of cell survival and death. Pancreatic cells exhibit high hormone and enzyme secretory functions, and thereby show a highly developed ER. Thus, pancreatic cancer cells display a prominent ER. Solid tumors have to cope with adverse situations in which hypoxia, lack of certain nutrients, and the action of certain antitumor agents lead to a complex interplay and crosstalk between ER stress and autophagy—the latter acting as an adaptive survival response. ER stress also mediates cell death induced by a number of anticancer drugs and experimental conditions, highlighting the pivotal role of ER stress in modulating cell fate. The alkylphospholipid analog prototype edelfosine is selectively taken up by tumor cells, accumulates in the ER of a number of human solid tumor cells—including pancreatic cancer cells—and promotes apoptosis through a persistent ER-stress-mediated mechanism both in vitro and in vivo. Here, we discuss and propose that direct ER targeting may be a promising approach in the therapy of pancreatic cancer, opening up a new avenue for the treatment of this currently incurable and deadly cancer. Furthermore, because autophagy acts as a cytoprotective response to ER stress, potentiation of the triggering of a persistent ER response by combination therapy, together with the use of autophagy blockers, could improve the current gloomy expectations for finding a cure for this type of cancer.

scholarly journals Bortezomib Inhibits PKR-Like Endoplasmic Reticulum (ER) Kinase and Induces Apoptosis via ER Stress in Human Pancreatic Cancer Cells

2005 ◽  
Vol 65 (24) ◽  
pp. 11510-11519 ◽  
Author(s):  
Steffan T. Nawrocki ◽  
Jennifer S. Carew ◽  
Kenneth Dunner ◽  
Lawrence H. Boise ◽  
Paul J. Chiao ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Cancer Cells ◽  
Human Pancreatic Cancer ◽  
Pancreatic Cancer Cells

scholarly journals Androgen-induced expression of endoplasmic reticulum (ER) stress response genes in prostate cancer cells

Oncogene ◽  
2002 ◽  
Vol 21 (57) ◽  
pp. 8749-8758 ◽  
Author(s):  
Takehiko Segawa ◽  
Martin E Nau ◽  
Linda L Xu ◽  
Rao N Chilukuri ◽  
Mazen Makarem ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Cancer Cells ◽  
Prostate Cancer Cells ◽  
Induced Expression ◽  
Er Stress Response ◽  
Stress Response Genes

scholarly journals Endoplasmic Reticulum Stress-Induced Formation of Transcription Factor Complex ERSF Including NF-Y (CBF) and Activating Transcription Factors 6α and 6β That Activates the Mammalian Unfolded Protein Response

2001 ◽  
Vol 21 (4) ◽  
pp. 1239-1248 ◽  
Author(s):  
Hiderou Yoshida ◽  
Tetsuya Okada ◽  
Kyosuke Haze ◽  
Hideki Yanagi ◽  
Takashi Yura ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factors ◽  
Stress Response ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Consensus Sequence ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
Protein Response ◽  
Transcriptional Induction

ABSTRACT The levels of molecular chaperones and folding enzymes in the endoplasmic reticulum (ER) are controlled by a transcriptional induction process termed the unfolded protein response (UPR). The mammalian UPR is mediated by the cis-acting ER stress response element (ERSE), the consensus sequence of which is CCAAT-N9-CCACG. We recently proposed that ER stress response factor (ERSF) binding to ERSE is a heterologous protein complex consisting of the constitutive component NF-Y (CBF) binding to CCAAT and an inducible component binding to CCACG and identified the basic leucine zipper-type transcription factors ATF6α and ATF6β as inducible components of ERSF. ATF6α and ATF6β produced by ER stress-induced proteolysis bind to CCACG only when CCAAT is bound to NF-Y, a heterotrimer consisting of NF-YA, NF-YB, and NF-YC. Interestingly, the NF-Y and ATF6 binding sites must be separated by a spacer of 9 bp. We describe here the basis for this strict requirement by demonstrating that both ATF6α and ATF6β physically interact with NF-Y trimer via direct binding to the NF-YC subunit. ATF6α and ATF6β bind to the ERSE as a homo- or heterodimer. Furthermore, we showed that ERSF including NF-Y and ATF6α and/or β and capable of binding to ERSE is indeed formed when the cellular UPR is activated. We concluded that ATF6 homo- or heterodimers recognize and bind directly to both the DNA and adjacent protein NF-Y and that this complex formation process is essential for transcriptional induction of ER chaperones.

Self-delivery of N-hydroxylethyl peptide assemblies to the cytosol inducing endoplasmic reticulum dilation in cancer cells

2019 ◽  
Vol 55 (52) ◽  
pp. 7474-7477 ◽  
Author(s):  
Shijin Zhang ◽  
Xunwu Hu ◽  
Dingze Mang ◽  
Toshio Sasaki ◽  
Ye Zhang
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Alcohol Abuse ◽  
Er Stress ◽  
Cancer Cells ◽  
Clinical Studies ◽  
Peptide Assembly ◽  
Er Stress Response

Inspired by clinical studies on alcohol abuse induced endoplasmic reticulum disruption, we designed a N-hydroxylethyl peptide assembly to regulate the ER stress response in cancer cells.

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