Evidence map›Paper›PMID 34381026›Full record

ArticleNature communications2021

GOT1 inhibition promotes pancreatic cancer cell death by ferroptosis.

Daniel M Kremer, Barbara S Nelson, Lin Lin, Emily L Yarosz, Christopher J Halbrook, Samuel A Kerk, Peter Sajjakulnukit, Amy Myers, Galloway Thurston, Sean W Hou and 24 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 167 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
167citing papers in PubMed, 1 pooled it
27.4field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

167 citing papers in PubMed, 1 synthesis or guideline pooled it, 244 citations in OpenAlex.

  1. Pooled it
  2. Review
  3. Ferroptosis in cancer: molecular mechanisms, biological roles, and therapeutic significance.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026
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107 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

34 authors at 5 institutions in 1 country.

Daniel M KremerDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0001-6224-0550
Barbara S NelsonGraduate Program in Cancer Biology, University of Michigan, Ann Arbor, MI, USA.
Lin LinDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Emily L YaroszImmunology Graduate Program, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0003-3201-9534
Christopher J HalbrookDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0002-3376-3114
Samuel A KerkGraduate Program in Cancer Biology, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0001-9786-2245
Peter SajjakulnukitGraduate Program in Cancer Biology, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0002-8556-7481
Amy MyersDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Galloway ThurstonDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Sean W HouDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Eileen S CarpenterDepartment of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA.
Anthony C AndrenDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Zeribe C NwosuDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0003-1641-2045
Nicholas CusmanoDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Stephanie WisnerDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Nneka E MbahDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Mengrou ShanDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Nupur K DasDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Brian MagnusonDepartment of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
Andrew C LittleRogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0003-0135-1032
Milan R SavaniMedical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, TX, USA.ORCID http://orcid.org/0000-0003-1776-451X
Johanna RamosDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Tina GaoDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Stephen A SastraDivision of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY, USA.
Carmine F PalermoDivision of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY, USA.
Michael A BadgleyDivision of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY, USA.
Li ZhangDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
John M AsaraDivision of Signal Transduction and Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Samuel K McBrayerChildren's Medical Center Research Institute and Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.ORCID http://orcid.org/0000-0001-9361-675X
Marina Pasca di MaglianoRogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
Howard C CrawfordDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Yatrik M ShahDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0002-2487-4816
Kenneth P OliveDivision of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY, USA.
Costas A LyssiotisDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA. clyssiot@med.umich.edu.ORCID http://orcid.org/0000-0001-9309-6141
University of Michigan · USColumbia University Irving Medical Center · USBeth Israel Deaconess Medical Center · USChildren's Medical Center · USThe University of Texas Southwestern Medical Center · US

Funding

XenograftP30CA046592 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI THEODORE S LAWRENCE · 1988 to 2026
$178.2M
University of Michigan Center for Gastrointestinal ResearchP30DK034933 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI OWYANG, CHUNG · 1986 to 2021
$22.5M
Pilot and Feasibility (P and F) ProgramP30DK089503 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Joyce Lee · 2010 to 2026
$20.3M
Training Program in Tumor MicroenvironmentT32CA009676 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Maria G Castro, Analisa Virginia DiFeo · 1992 to 2026
$7.3M
Control of iron absorption by intestinal HIF2 in iron and hematological disordersR01DK095201 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI SHAH, YATRIK M · 2012 to 2025
$5.7M
The role of HIF2alpha in colon carcinogenesisR01CA148828 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI SHAH, YATRIK M · 2010 to 2025
$5.2M
Targeting cysteine import to induce ferroptotic cell death in pancreatic cancerR01CA215607 · NCI · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI Kenneth P. Olive · 2017 to 2026
$4.0M
Proteogenomics of Cancer Training ProgramT32CA140044 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI RAO, ARVIND, SARTOR, MAUREEN AGNES · 2010 to 2024
$3.9M
Training in Basic and Translational Digestive SciencesT32DK094775 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI JOHN Y KAO, LINDA C. SAMUELSON · 2012 to 2026
$3.6M
Mechanisms of Pancreatic Inflammation, Tissue Repair and CarcinogenesisR01CA151588 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI PASCA DI MAGLIANO, MARINA · 2010 to 2020
$3.3M
Interrupting Cellular Crosstalk in the Immunosuppressive Microenvironment of Pancreas CancerU01CA224145 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI CRAWFORD, HOWARD C., PASCA DI MAGLIANO, MARINA · 2017 to 2021
$2.6M
Intratumoral Metabolic Crosstalk Promotes Therapeutic Resistance in Pancreatic CancerR37CA237421 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Costas Andreas Lyssiotis · 2020 to 2026
$2.6M
NCI NIH HHS K22 CA237752NCI NIH HHS P30 CA046592NCI NIH HHS R01 CA148828NCI NIH HHS R01 CA151588NCI NIH HHS R01 CA198074NCI NIH HHS R01 CA215607NCI NIH HHS R01 CA244931NCI NIH HHS R01 CA245546NCI NIH HHS R01 CA248160NCI NIH HHS R37 CA237421NCI NIH HHS T32 CA009676NCI NIH HHS T32 CA140044NCI NIH HHS U01 CA224145NIDDK NIH HHS P30 DK034933NIDDK NIH HHS P30 DK089503NIDDK NIH HHS R01 DK095201NIDDK NIH HHS T32 DK094775
6 · The paper itself

Abstract

Cancer metabolism is rewired to support cell survival in response to intrinsic and environmental stressors. Identification of strategies to target these adaptions is an area of active research. We previously described a cytosolic aspartate aminotransaminase (GOT1)-driven pathway in pancreatic cancer used to maintain redox balance. Here, we sought to identify metabolic dependencies following GOT1 inhibition to exploit this feature of pancreatic cancer and to provide additional insight into regulation of redox metabolism. Using pharmacological methods, we identify cysteine, glutathione, and lipid antioxidant function as metabolic vulnerabilities following GOT1 withdrawal. We demonstrate that targeting any of these pathways triggers ferroptosis, an oxidative, iron-dependent form of cell death, in GOT1 knockdown cells. Mechanistically, we reveal that GOT1 inhibition represses mitochondrial metabolism and promotes a catabolic state. Consequently, we find that this enhances labile iron availability through autophagy, which potentiates the activity of ferroptotic stimuli. Overall, our study identifies a biochemical connection between GOT1, iron regulation, and ferroptosis.

Indexed as

FerroptosisAnimalsAntioxidantsAspartate Aminotransferase, CytoplasmicCell Line, TumorCell ProliferationCell SurvivalCystineGlutathioneHumansIronMiceMitochondriaPancreatic NeoplasmsAntioxidantsAspartate Aminotransferase, CytoplasmicCystineGlutathioneGOT1 protein, humanIron

Identifiers

PMID34381026
PMCPMC8357841
OpenAlexW3187333436

What OpenQuestion holds

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LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.