Expression and roles of NUPR1 in cholangiocarcinoma cells

Kim, Ki-Sun; Jin, Du-Il; Yoon, Sik; Baek, Sun‐Yong; Kim, Bong-Seon; Oh, Sae‐Ock

doi:10.5115/acb.2012.45.1.17

Cited by 20 publications

(18 citation statements)

References 33 publications

(42 reference statements)

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“…NUPR1-dependent effects also mediate resistance to anticancer drugs (Giroux et al, 2006;Palam et al, 2015;Tang et al, 2011), an important characteristic of this malignancy. We (Sandi et al, 2011;Vasseur et al, 2002b) and others (Emma et al, 2016;Guo et al, 2012;Kim et al, 2012;Li et al, 2017;Zeng et al, 2017) have shown that genetic inactivation of Nupr1 antagonizes the growth of tumors in several tissues, including pancreatic cancer (Sandi et al, 2011) thereby supporting a role for this protein as a promising therapeutic target for the development of therapies for pancreatic cancer. Congruently, using a comprehensive approach that combines biophysical, biochemical, computational, and biological methods for repurposing FDA approved drugs in the treatment of pancreatic cancer, we have recently identified that the phenothiazine derivative, trifluoperazine, mimics the effect of the genetic inactivation of NUPR1, revealing its anticancer properties (Neira et al, 2017).…”

Section: Introductionmentioning

confidence: 72%

“…Several empiric observations have shown that cancer cells undergo growth arrest or cell death after genetic inactivation of NUPR1 in vitro and in vivo (Emma et al, 2016;Guo et al, 2012;Kim et al, 2012;Li et al, 2017;Sandi et al, 2011;Vasseur et al, 2002b). However, to date, the mechanisms responsible for the biological consequences of its inactivation in cancer cells remain poorly understood.…”

Section: Discussionmentioning

confidence: 99%

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

Iovanna

Santofimia‐Castaño

Lan

et al. 2018

Preprint

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HighlightsNUPR1 expression promotes pancreatic cancer development and progression NUPR1-depletion is a promising therapeutic strategy to be used for treating cancers NUPR1-depletion induces ER stress, mitochondrial malfunction and a significant switch from OXPHOS to glycolysis followed by necrotic cell death Inactivation of NUPR1 antagonizes cell growth by coupling a defective ER-stress response and a caspase-independent necrosis.. CC-BY-NC-ND 4.0 International license not peer-reviewed) is the author/funder. It is made available under aThe copyright holder for this preprint (which was . http://dx.doi.org/10.1101/277384 doi: bioRxiv preprint first posted online Mar. 6, 2018; 3 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 Ca 2+ 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.

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Section: Introductionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

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

Iovanna

Santofimia‐Castaño

Lan

et al. 2018

Preprint

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“…Histopathologic diagnoses of CCA were performed at the Department of Pathology, Pusan National University Hospital. Tissues were deparaffinized, rehydrated, and washed using xylene, ethanol, and PBS, respectively, and then antigen retrieval was performed using the citrate buffer as previously described [21]. Endogenous peroxidase activity was inactivated with 3% hydrogen peroxide for 15min.…”

Section: Methodsmentioning

confidence: 99%

ZHX1 Promotes the Proliferation, Migration and Invasion of Cholangiocarcinoma Cells

et al. 2016

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Zinc-fingers and homeoboxes 1 (ZHX1) is a transcription repressor that has been associated with the progressions of hepatocellular carcinoma, gastric cancer, and breast cancer. However, the functional roles of ZHX1 in cholangiocarcinoma (CCA) have not been determined. We investigated the expression and roles of ZHX1 during the proliferation, migration, and invasion of CCA cells. In silico analysis and immunohistochemical studies showed amplification and overexpression of ZHX1 in CCA tissues. Furthermore, ZHX1 knockdown using specific siRNAs decreased CCA cell proliferation, migration, and invasion, whereas ZHX1 overexpression promoted all three characteristics. In addition, results suggested EGR1 might partially mediate the effect of ZHX1 on the proliferation of CCA cells. Taken together, these results show ZHX1 promotes CCA cell proliferation, migration, and invasion, and present ZHX1 as a potential target for the treatment of CCA.

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“…Notably, NUPR1-dependent effects also mediate resistance to anticancer drugs (14)(15)(16). We previously showed that genetic inactivation of Nupr1 antagonizes the growth of pancreatic cancer (10,17), and other laboratories have also shown that genetic inactivation of Nupr1 stops the growth of hepatocarcinoma (18), non-small cell lung cancer (19), cholangiocarcinoma (20), glioblastoma (21), multiple myeloma (22)(23), and osteosarcoma (24), thereby supporting this protein's role as a promising therapeutic target for developing new cancer therapies.…”

Section: Introductionmentioning

confidence: 99%

Ligand-based design identifies a potent NUPR1 inhibitor exerting anticancer activity via necroptosis

Santofimia‐Castaño¹,

Xia²,

Lan³

et al. 2019

Journal of Clinical Investigation

102

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Expression and roles of NUPR1 in cholangiocarcinoma cells

Cited by 20 publications

References 33 publications

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

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

ZHX1 Promotes the Proliferation, Migration and Invasion of Cholangiocarcinoma Cells

Ligand-based design identifies a potent NUPR1 inhibitor exerting anticancer activity via necroptosis

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