For Publishers
DiscoveryMetadataPeer reviewHostingPublishing
For Researchers
JoinPublishReviewCollect
Register
Blog
About
Search
Advanced search
My ScienceOpen
Search
For Publishers
For Researchers
Blog
About
60
views
16
references
 Top references
cited by
497
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
0 collections
    0
    shares
      544
      similar
       All similar
      • Record: found
      • Abstract: found
      • Article: not found

      Cysteine depletion induces pancreatic tumor ferroptosis in mice

      Author(s): 1 , 2 , 3 , 4 , 1 , 2 , 5 , 6 , 3 , 4 , 3 , 4 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 7 , 3 , 4 , 4 , 8 , 3 , 4 , 9 , 10 , 2 , 11 , 12 , 2 , 11 , 12 , 13 , 14 , 10 , 15 , 15 , 7 , 2 , 12 , 6 , 9 , 3 , 4 , 16 , 1 , 2
      Publication date Created:
      Publication date (Electronic):
      Journal: Science
      Publisher: American Association for the Advancement of Science (AAAS)

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Ferroptosis is a form of cell death that results from the catastrophic accumulation of lipid reactive oxygen species (ROS). Oncogenic signaling elevates lipid ROS production in many tumor types and is counteracted by metabolites that are derived from the amino acid cysteine. In this work, we show that the import of oxidized cysteine (cystine) via system x C – is a critical dependency of pancreatic ductal adenocarcinoma (PDAC), which is a leading cause of cancer mortality. PDAC cells used cysteine to synthesize glutathione and coenzyme A, which, together, down-regulated ferroptosis. Studying genetically engineered mice, we found that the deletion of a system x C – subunit, Slc7a11, induced tumor-selective ferroptosis and inhibited PDAC growth. This was replicated through the administration of cyst(e)inase, a drug that depletes cysteine and cystine, demonstrating a translatable means to induce ferroptosis in PDAC.

          Related collections

          Most cited references16

          • Record: found
          • Abstract: found
          • Article: not found

          Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma

          Richard A Moffitt, Raoud Marayati, Elizabeth Flate … (2015)
          Pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease with a 5-year survival of 4%. A key hallmark of PDAC is extensive stromal involvement, which makes capturing precise tumor-specific molecular information difficult. Here, we have overcome this problem by applying blind source separation to a diverse collection of PDAC gene expression microarray data, which includes primary, metastatic, and normal samples. By digitally separating tumor, stroma, and normal gene expression, we have identified and validated two tumor-specific subtypes including a “basal-like” subtype which has worse outcome, and is molecularly similar to basal tumors in bladder and breast cancer. Furthermore, we define “normal” and “activated” stromal subtypes which are independently prognostic. Our results provide new insight into the molecular composition of PDAC which may be used to tailor therapies or provide decision support in a clinical setting where the choice and timing of therapies is critical.
          Article 0 comments Cited 790 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            FKBP51 affects cancer cell response to chemotherapy by negatively regulating Akt.

            Huadong Pei, Liang Li, Brooke Fridley … (2009)
            Akt is a central regulator of cell growth. Its activity can be negatively regulated by the phosphatase PHLPP that specifically dephosphorylates the hydrophobic motif of Akt (Ser473 in Akt1). However, how PHLPP is targeted to Akt is not clear. Here we show that FKBP51 (FK506-binding protein 51) acts as a scaffolding protein for Akt and PHLPP and promotes dephosphorylation of Akt. Furthermore, FKBP51 is downregulated in pancreatic cancer tissue samples and several cancer cell lines. Decreased FKBP51 expression in cancer cells results in hyperphosphorylation of Akt and decreased cell death following genotoxic stress. Overall, our findings identify FKBP51 as a negative regulator of the Akt pathway, with potentially important implications for cancer etiology and response to chemotherapy.
            Article 0 comments Cited 322 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              A Novel MIF Signaling Pathway Drives the Malignant Character of Pancreatic Cancer by Targeting NR3C2

              Shouhui Yang, Peijun He, Jian Wang … (2016)
              Pancreatic cancers with aberrant expression of macrophage migration inhibitory factor (MIF) are particularly aggressive. To identify key signaling pathways that drive disease aggressiveness in tumors with high MIF expression, we analyzed the expression of coding and non-coding genes in high and low MIF-expressing tumors in multiple cohorts of pancreatic ductal adenocarcinoma (PDAC) patients. The key genes and pathways identified were linked to patient survival and were mechanistically, functionally and clinically characterized using cell lines, a genetically engineered mouse model and PDAC patient cohorts. Here we report evidence of a novel MIF-driven signaling pathway that inhibits the orphan nuclear receptor NR3C2, a previously undescribed tumor suppressor that impacts aggressiveness and survival in PDAC. Mechanistically, MIF upregulated miR-301b which targeted NR3C2 and suppressed its expression. PDAC tumors expressing high levels of MIF displayed elevated levels of miR-301b and reduced levels of NR3C2. Additionally, reduced levels of NR3C2 expression correlated with poorer survival in multiple independent cohorts of PDAC patients. Functional analysis showed that NR3C2 inhibited epithelial-to-mesenchymal transition and enhanced sensitivity to the gemcitabine, a chemotherapeutic drug used in PDAC standard of care. Furthermore, genetic deletion of MIF disrupted a MIF-mir-301b-NR3C2 signaling axis, reducing metastasis and prolonging survival in a genetically engineered mouse model of PDAC. Taken together, our results offer a preclinical proof-of-principle for candidate therapies to target a newly described MIF-miR-301b-NR3C2 signaling axis for PDAC management.
              Article 0 comments Cited 143 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Journal
                Title: Science
                Abbreviated Title: Science
                Publisher: American Association for the Advancement of Science (AAAS)
                ISSN (Print): 0036-8075
                ISSN (Electronic): 1095-9203
                Publication date Created: April 02 2020
                Publication date Created: April 03 2020
                Publication date (Electronic): April 02 2020
                Publication date (Print): April 03 2020
                Volume: 368
                Issue: 6486
                Pages: 85-89
                Affiliations
                [1 ]Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.
                [2 ]Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
                [3 ]Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
                [4 ]Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
                [5 ]Klinikum rechts der Isar, II, Medizinische Klinik, Technische Universität München, 81675, Munich, Germany.
                [6 ]Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
                [7 ]Waitt Advanced Biophotonics Center, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
                [8 ]Michigan Regional Comprehensive Metabolomics Resource Core, University of Michigan, Ann Arbor, MI 48105, USA.
                [9 ]Departments of Biological Sciences and Chemistry, Columbia University, New York, NY 10027, USA.
                [10 ]Department of Chemical Engineering, University of Texas at Austin, Austin, TX 78712, USA.
                [11 ]Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10032, USA.
                [12 ]Department of Pathology, Columbia University Medical Center, New York, NY 10032, USA.
                [13 ]Department of Pathology, University of California, San Francisco, CA 94143, USA.
                [14 ]Salvo Therapeutics, San Francisco, CA 94117, USA.
                [15 ]Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA.
                [16 ]Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109, USA.
                Article
                DOI: 10.1126/science.aaw9872
                PMC ID: 7681911
                PubMed ID: 32241947
                SO-VID: 4d2ae5b9-1290-4a17-abbf-f85635bc8d48
                Copyright © © 2020
                License:

                http://www.sciencemag.org/about/science-licenses-journal-article-reuse

                History

                Data availability:

                Comments

                Comment on this article

                scite_

                Similar content544

                See all similar

                Cited by505

                See all cited by

                Most referenced authors1,653

                See all reference authors