Glutamine transporters regulate prostate cancer radiosensitivity through NUPR1-mediated stress response
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PROVIDER: PRJNA1219126 | ENA |
REPOSITORIES: ENA
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Project description:Prostate cancer (PCa) presents a significant clinical challenge due to its resistance to conventional therapies such as radiotherapy (RT), which is exacerbated in advanced stages by metabolic and stress response adaptations. Our study investigates the roles of amino acid transporters SLC1A5, SLC7A5, and SLC38A1, in regulating NUPR1-mediated stress response, PCa cell survival, metabolic reprogramming, and response to RT. Depletion of these transporters disrupted glutamine (Gln) uptake, leading to reduced cell viability, altered ROS levels, and enhanced radiosensitivity in DU145 and LNCaP cell lines. Functional assays revealed that targeting these transporters decreases stem cell-like properties, impairs cell cycle progression, and heightens DNA damage under RT. Besides, CB839, a glutaminase inhibitor, combined with RT, demonstrated a synergistic effect in vivo, significantly delaying tumor growth compared to other treatment groups. Our findings indicate that these transporters mediate PCa cells’ adaptation to nutrient stress, while NUPR1 promotes cellular survival under metabolic and genotoxic stress. The results highlight the therapeutic potential of targeting Gln metabolism and stress response pathways to improve treatment efficacy. Our findings indicate that targeting SLC1A5, SLC7A5, SLC38A1, and NUPR1 radiosensitizes PCa by disrupting metabolic adaptations and stress responses. These findings provide a potential therapeutic strategy to enhance the efficacy of RT and improve treatment outcomes for PCa patients.
2025-07-30 | GSE288717 | GEO
Project description:Nuclear Protein 1 (NUPR1) is a nuclear intrinsically disordered protein of 82 amino acids that plays an important role in stress response and in cancer development. The project was aimed at identifying binding partners of NUPR1 in MiaPaCa-2 cells, in control and after stress condition: glucose starvation during 24h. Lysates from MiaPaCa-2 cells (transfected with NUPR1-Flag or NUPR1-GFP) were used for immunoprecipitation, performed with agarose beads coated with anti-Flag or anti-GFP antibodies. After immunoprecipitation, the eluted proteins were analyzed by LC-MS/MS.
2022-07-29 | PXD035236 | Pride
Project description:we uncovered that nuclear protein 1 (Nupr1), a transcription regulatory gene preferentially expressed in HECs, was a negative regulator of EHT. Nupr1 deficiency resulted in plentiful emergence of HSC-competent cells in the AGM region, including HECs and HSPCs. Further single-cell transcriptome combined serial functional assay revealed that loss of Nupr1 prominently accelerate EHT process, also promote the specification of HECs and strengthen their subsequent hematopoietic differentiation potential towards HSPC. Interestingly, we found that numerous inflammatory signals were specifically upregulated in Nupr1-/- EHT relevant populations, as elevated inflammatory response signals have been proved to promote EHT and HSPCs generation.
2022-06-10 | GSE205595 | GEO
Project description:To support cellular homeostasis and mitigate chemotherapeutic stress, cancer cells must gain a series of adaptive intracellular processes. Here we identify that NUPR1, a tamoxifen (Tam)-induced transcriptional coregulator, is necessary for the maintenance of Tam resistance through physical interaction with ESR1 in breast cancers. Mechanistically, NUPR1 binds to the promoter regions of several genes involved in autophagy process and drug resistance such as BECN1, GREB1, RAB31, PGR, CYP1B1, and regulates their transcription. In Tam-resistant ESR1 breast cancer cells, NUPR1 depletion results in premature senescence in vitro and tumor suppression in vivo. Moreover, enforced-autophagic flux augments cytoplasmic vacuolization in NUPR1-depleted Tam resistant cells, which facilitates the transition from autophagic survival to premature senescence. Collectively, these findings suggest a critical role for NUPR1 as a transcriptional coregulator in enabling endocrine persistence of breast cancers, thus providing a vulnerable diagnostic and/or therapeutic target for endocrine resistance.
2018-04-27 | GSE104050 | GEO
Project description:In the advanced stages of cancer, autophagy is thought to promote tumor progression through its ability to mitigate various cellular stresses. However, the details of how autophagy is homeostatically regulated in such tumors are unknown. Here, we report that NUPR1 (nuclear protein 1, transcriptional regulator), a transcriptional coregulator, is aberrantly expressed in a subset of cancer cells and predicts low overall survival rates for lung cancer patients. NUPR1 regulates the late stages of autolysosome processing through the induction of the SNARE protein SNAP25, which forms a complex with the lysosomal SNARE associated protein VAMP8. NUPR1 depletion deregulates autophagic flux and impairs autolysosomal clearance, inducing massive cytoplasmic vacuolization and premature senescence in vitro and tumor suppression in vivo. Collectively, our data show that NUPR1 is a potent regulator of autolysosomal dynamics and is required for the progression of some epithelial cancers.
2016-06-05 | GSE68873 | GEO
Project description:The objective of this study was to elucidate the role of Nupr1 in pancreatic tumorigenesis. Using the Pdx-1-cre;LSL-KrasG12D mouse as model we discovered that, in contrast to KrasG12D pancreas that develop multiple foci of pancreatic intraepithelial neoplasia (PanIN), KrasG12D;Nupr1KO pancreas were free from such lesions, indicating that Nupr1 is pivotal for PanIN formation. In vitro, MiaPaCa2 cells activated Nupr1 expression in response to nutrient deprivation and this expression was necessary for cell survival. Mechanistically, Nupr1 protected cells from stress-induced death by inhibiting apoptosis through an alternative RelBàIER3-dependent pathway and independent from activation of the classical RelA-based NF-kB pathway. In agreement with these findings, Nupr1, RelB and IER3 proteins were found co-expressed in PanINs from KrasG12D pancreas. Moreover, pancreas-specific KrasG12D;RelbDpanc mice displayed a delay in PanIN development associated with a lack of IER3 expression, further emphasizing the relevance of this pathway in vivo. Efficient PanIN formation was therefore dependent on the expression of Nupr1 and RelB, with the probable involvement of IER3. Finally, a significant correlation between expression of Nupr1, RelB and IER3 and a poor prognosis of patients with PDAC was found. Altogether, our results reveal a novel stress-related pathway that requires the functional interaction of Nupr1àRelBàIER3 in KrasG12D-dependent transformation of the pancreas and expand our understanding of the molecular machinery that mediates the early steps of pancreatic carcinogenesis. Since Nupr1 belongs to the HMG family of chromatin remodelers with transcriptional co-factor activity, Nupr1 could increase cell survival in a nutrient-deprived microenvironment by activating the expression of pro-survival genes. Moreover, considering that RelB, and not RelA/p65, is essential to the Nupr1-mediated survival mechanism that takes place upon nutrient deprivation-induced stress, we made the hypothesis that the two NF-kB transcription factors should activate different sets of genes among which a pivotal pro-survival gene would be exclusively dependent on RelB. In order to test this two hypothesis, an Affymetrix microarray analysis was performed using pancreatic cancer cells transfected with siCtrl or siNupr1 and cultured for 3, 6 or 9 hrs in EBSS; or transfected with siRelB, siRelA/p65 or siCtrl and cultured for 9 hrs in EBSS or Mock.
2012-02-01 | E-GEOD-35463 | biostudies-arrayexpress
Project description:Sorafenib, an oral multikinase inhibitor, is the only approved agent for the treatment of advanced hepatocellular carcinoma (HCC). However, its benefits is modest, also because its mechanism of action remains elusive, therefore, a better understanding of its molecular action and molecular targets are needed. On the basis of our previous studies, here, we investigated the role of the nuclear protein 1 (NUPR1) in HCC and its role in the context of sorafenib treatment. NUPR1 is a stress-inducible protein over-expressed in different malignancies, however, its role in HCC is not yet fully understood. We found that NUPR1, is over-expressed in 53% of primary human HCC samples. Knockdown of NUPR1 significantly increased cell sensitivity to sorafenib and inhibits cell growth, migration and invasion of HCC cells in vitro and tumorigenicity in vivo. Moreover, NUPR1 silencing influenced expression of target genes RelB and IER3. Unsurprisingly, RelB and IER3 knockdown also inhibited HCC cells viability, growth and migration. By gene expression profiling of HCC cells following stable NUPR1 knockdown, we found that genes functionally involved in cell death and survival, cellular response to therapies, lipid metabolism, cell growth and proliferation, molecular transport and cellular movement were mostly suppressed. Network analysis of dynamic gene expression identified NF-κB and ERK as down-regulated gene nodes, and several genes known to be involved in hepatocarcinogenesis were also suppressed. In addition, we identified Runt-related transcription factor 2 (RUNX2) gene as a NUPR1 down-regulated gene. We also demonstrated that RUNX2 gene silencing inhibited HCC cells viability, growth, migration and increased cell sensitivity to sorafenib. Conclusion: We propose that NUPR1/RELB/IER3/RUNX2 pathway play pivotal role in hepatocarcinogenesis. The identification of NUPR1/RELB/IER3/RUNX2 pathway as a potential therapeutic target may contribute to the development of new treatment strategies for HCC management. To better understand the molecular mechanisms of NUPR1 gene action in ovarian HCC cells, we employed the Agilent Whole Human Genome microarrays, containing ~ 44,000 genes to identify global gene expression changes upon NUPR1 suppression in HCC cells. We compared the gene expression of the previously selected shRNA-mediated NURP1-knockdown Hep3B clone against the corresponding control (ctrl) clone. The microarray experiments were performed in duplicates, as two hybridizations were carried out for the NUPR1-suppressing cell clone against the corresponding control, using a fluorescent dye reversal (dye-swap) technique.
2016-06-15 | E-GEOD-73521 | biostudies-arrayexpress
Project description:The majority of prostate cancer (PCa) patients treated with docetaxel develop resistance to it. In order to better understand the mechanism behind the acquisition of resistance, we conducted single cell total RNA sequencing (sctotal RNA-seq) of docetaxel sensitive and resistant variants of DU145 and PC3 PCa cell lines. Overall, sensitive and resistant cells clustered separately. However, for both cell lines we identified rare sensitive cells that clustered with the resistant cells indicating resistant cells pre-exist in the sensitive population. Differential gene expression analysis between resistant and sensitive cells revealed 182 differentially expressed genes common to both PCa cell lines. A subset of these genes gave a gene expression profile in the resistant-like sensitive cells similar to the resistant cells. Exploration for functional gene pathways identified 218 common pathways between the two cell lines. Protein ubiquitination was the most differentially regulated pathway and was enriched in the resistant cells. Transcriptional regulator analysis identified potential 321 regulators across both cell lines. One of the top regulators identified was nuclear protein 1 (NUPR1). In contrast to the single cell analysis, bulk analysis of the cells did not reveal NUPR1 as a promising candidate. Knockdown and overexpression of NUPR1 in the PCa cells demonstrated that NUPR1 confers docetaxel resistance in both cell lines. Collectively, these data demonstrate the utility of sctotal RNA-seq to identify regulators of drug resistance. Furthermore, NUPR1 was identified as a mediator of PCa drug resistance, which provides the rationale to explore NUPR1 and its target genes to for reversal of docetaxel resistance.
2020-09-01 | GSE140440 | GEO
Project description:The objective of this study was to elucidate the role of Nupr1 in pancreatic tumorigenesis. Using the Pdx-1-cre;LSL-KrasG12D mouse as model we discovered that, in contrast to KrasG12D pancreas that develop multiple foci of pancreatic intraepithelial neoplasia (PanIN), KrasG12D;Nupr1KO pancreas were free from such lesions, indicating that Nupr1 is pivotal for PanIN formation. In vitro, MiaPaCa2 cells activated Nupr1 expression in response to nutrient deprivation and this expression was necessary for cell survival. Mechanistically, Nupr1 protected cells from stress-induced death by inhibiting apoptosis through an alternative RelBàIER3-dependent pathway and independent from activation of the classical RelA-based NF-kB pathway. In agreement with these findings, Nupr1, RelB and IER3 proteins were found co-expressed in PanINs from KrasG12D pancreas. Moreover, pancreas-specific KrasG12D;RelbDpanc mice displayed a delay in PanIN development associated with a lack of IER3 expression, further emphasizing the relevance of this pathway in vivo. Efficient PanIN formation was therefore dependent on the expression of Nupr1 and RelB, with the probable involvement of IER3. Finally, a significant correlation between expression of Nupr1, RelB and IER3 and a poor prognosis of patients with PDAC was found. Altogether, our results reveal a novel stress-related pathway that requires the functional interaction of Nupr1àRelBàIER3 in KrasG12D-dependent transformation of the pancreas and expand our understanding of the molecular machinery that mediates the early steps of pancreatic carcinogenesis.
2012-02-01 | GSE35463 | GEO
Project description:This study confirmed the radiosensitizing effects of surufatinib on cholangiocarcinoma. The mechanism is that surufatinib can activate TLR3, up-regulate the expression of TRIF protein, increase DNA damage and apoptosis after radiation, and up-regulate NF- κB signal pathway to inhibit M2 polarization of tumor-associated macrophages, thus enhance radiosensitivity.
2024-06-30 | GSE269494 | GEO