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

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.

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

Journal of Biological Chemistry ◽

10.1074/jbc.c500030200 ◽

2005 ◽

Vol 280 (16) ◽

pp. 16508-16513 ◽

Cited By ~ 23

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.

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

Cancers ◽

10.3390/cancers13164173 ◽

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.

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

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00466.2013 ◽

2014 ◽

Vol 306 (11) ◽

pp. G1011-G1020 ◽

Cited By ~ 29

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.

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

10.1101/187484 ◽

2017 ◽

Cited By ~ 1

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.

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Galectin-3 is modulated in pancreatic cancer cells under hypoxia and nutrient deprivation

Biological Chemistry ◽

10.1515/hsz-2019-0413 ◽

2020 ◽

Vol 401 (10) ◽

pp. 1153-1165 ◽

Cited By ~ 2

Author(s):

Antônio F. da Silva Filho ◽

Lucas B. Tavares ◽

Maira G. R. Pitta ◽

Eduardo I. C. Beltrão ◽

Moacyr J. B. M. Rêgo

Keyword(s):

Pancreatic Cancer ◽

Cell Death ◽

Mrna Expression ◽

Cancer Cells ◽

Ductal Adenocarcinoma ◽

Reverse Transcription Pcr ◽

Pancreatic Cancer Cells ◽

Through Flow ◽

Galectin 3

AbstractPancreatic ductal adenocarcinoma is one of the most aggressive tumors with a microenvironment marked by hypoxia and starvation. Galectin-3 has been evaluated in solid tumors and seems to present both pro/anti-tumor effects. So, this study aims to characterize the expression of Galectin-3 from pancreatic tumor cells and analyze its influence for cell survive and motility in mimetic microenvironment. For this, cell cycle and cell death were accessed through flow cytometry. Characterization of inside and outside Galectin-3 was performed through Real-Time Quantitative Reverse Transcription PCR (qRT-PCR), immunofluorescence, Western blot, and ELISA. Consequences of Galectin-3 extracellular inhibition were investigated using cell death and scratch assays. PANC-1 showed increased Galectin-3 mRNA expression when cultivated in hypoxia for 24 and 48 h. After 24 h in simultaneously hypoxic/deprived incubation, PANC-1 shows increased Galectin-3 protein and secreted levels. For Mia PaCa-2, cultivation in deprivation was determinant for the increasing in Galectin-3 mRNA expression. When cultivated in simultaneously hypoxic/deprived condition, Mia PaCa-2 also presented increasing for the Galectin-3 secreted levels. Treatment of PANC-1 cells with lactose increased the death rate when cells were incubated simultaneously hypoxic/deprived condition. Therefore, it is possible to conclude that the microenvironmental conditions modulate the Galectin-3 expression on the transcriptional and translational levels for pancreatic cancer cells.

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Bak expression and cell death occur in peritumorous tissue but not in pancreatic cancer cells,

Journal of Gastrointestinal Surgery ◽

10.1016/s1091-255x(99)80012-2 ◽

1999 ◽

Vol 3 (1) ◽

pp. 74-81 ◽

Cited By ~ 12

Author(s):

H Graber

Keyword(s):

Pancreatic Cancer ◽

Cell Death ◽

Cancer Cells ◽

Pancreatic Cancer Cells

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ER stress compromises VEGFA secretion of pancreatic cancer cells under hypoxic conditions, thereby contributing to tumor hypoxia

HPB ◽

10.1016/j.hpb.2016.01.431 ◽

2016 ◽

Vol 18 ◽

pp. e837

Author(s):

B. Kong ◽

T. Cheng ◽

I. Regel ◽

S. Raulefs ◽

H. Friess ◽

...

Keyword(s):

Pancreatic Cancer ◽

Er Stress ◽

Cancer Cells ◽

Tumor Hypoxia ◽

Hypoxic Conditions ◽

Pancreatic Cancer Cells

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Necroptosis in Immuno-Oncology and Cancer Immunotherapy

Cells ◽

10.3390/cells9081823 ◽

2020 ◽

Vol 9 (8) ◽

pp. 1823 ◽

Cited By ~ 2

Author(s):

Jenny Sprooten ◽

Pieter De Wijngaert ◽

Isaure Vanmeerbeek ◽

Shaun Martin ◽

Peter Vangheluwe ◽

...

Keyword(s):

Cell Death ◽

Cancer Cells ◽

Cancer Immunotherapy ◽

Inflammatory Cell ◽

Necrotic Cell Death ◽

Immunogenic Cell Death ◽

Necrotic Cell ◽

Cell Death Pathway ◽

Immune Checkpoint Blockers ◽

Anticancer Immunity

Immune-checkpoint blockers (ICBs) have revolutionized oncology and firmly established the subfield of immuno-oncology. Despite this renaissance, a subset of cancer patients remain unresponsive to ICBs due to widespread immuno-resistance. To “break” cancer cell-driven immuno-resistance, researchers have long floated the idea of therapeutically facilitating the immunogenicity of cancer cells by disrupting tumor-associated immuno-tolerance via conventional anticancer therapies. It is well appreciated that anticancer therapies causing immunogenic or inflammatory cell death are best positioned to productively activate anticancer immunity. A large proportion of studies have emphasized the importance of immunogenic apoptosis (i.e., immunogenic cell death or ICD); yet, it has also emerged that necroptosis, a programmed necrotic cell death pathway, can also be immunogenic. Emergence of a proficient immune profile for necroptosis has important implications for cancer because resistance to apoptosis is one of the major hallmarks of tumors. Putative immunogenic or inflammatory characteristics driven by necroptosis can be of great impact in immuno-oncology. However, as is typical for a highly complex and multi-factorial disease like cancer, a clear cause versus consensus relationship on the immunobiology of necroptosis in cancer cells has been tough to establish. In this review, we discuss the various aspects of necroptosis immunobiology with specific focus on immuno-oncology and cancer immunotherapy.

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