Evidence map›Paper›PMID 27362805›Full record

ArticleCell death & disease2016

Tubular epithelial cells in renal clear cell carcinoma express high RIPK1/3 and show increased susceptibility to TNF receptor 1-induced necroptosis.

R S Al-Lamki, W Lu, P Manalo, J Wang, A Y Warren, A M Tolkovsky, J S Pober, J R Bradley

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

Article in Cell death & disease, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.

0numbers the graph read from it
0cells of the map it votes in
30citing papers in PubMed
1.4field-weighted citation impact, top 18% 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

30 citing papers in PubMed, 47 citations in OpenAlex.

  1. Article
  2. Article
  3. Targeting RIPK1 to modulate cell death and tumour microenvironment in cancer therapy.Journal of enzyme inhibition and medicinal chemistry · 2025
    Review
  4. Article
  5. Review
  6. The role of ZBP1 in eccentric exercise-induced skeletal muscle necroptosis.Journal of muscle research and cell motility · 2023
    Article
  7. Article
  8. Article
  9. Article
  10. Review
  11. Article
  12. Review
  13. Article
  14. No Time to Die: How Kidney Cancer Evades Cell Death.International journal of molecular sciences · 2022
    Review
  15. Article
  16. Article
  17. Article
  18. Article
  19. Article
  20. Article
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

8 authors at 3 institutions in 2 countries.

R S Al-LamkiDepartment of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
W LuDepartment of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
P ManaloDepartment of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
J WangDepartment of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
A Y WarrenDepartment of Pathology, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
A M TolkovskyDepartment of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
J S PoberDepartment of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA.
J R BradleyDepartment of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
University of Cambridge · GBAddenbrooke's Hospital · GBYale University · US

Funding

PROTEINS OF THE ENDOTHELIAL CELL SURFACER01HL036003 · NHLBI · YALE UNIVERSITY · PI KLUGER, MARTIN S, POBER, JORDAN S · 1985 to 2015
$5.7M
NHLBI NIH HHS R01 HL036003
6 · The paper itself

Abstract

We previously reported that renal clear cell carcinoma cells (RCC) express both tumor necrosis factor receptor (TNFR)-1 and -2, but that, in organ culture, a TNF mutein that only engages TNFR1, but not TNFR2, causes extensive cell death. Some RCC died by apoptosis based on detection of cleaved caspase 3 in a minority TUNEL-positive cells but the mechanism of death in the remaining cells was unexplained. Here, we underpin the mechanism of TNFR1-induced cell death in the majority of TUNEL-positive RCC cells, and show that they die by necroptosis. Malignant cells in high-grade tumors displayed threefold to four fold higher expression of both receptor-interacting protein kinase (RIPK)1 and RIPK3 compared with non-tumor kidney tubular epithelium and low-grade tumors, but expression of both enzymes was induced in lower grade tumors in organ culture in response to TNFR1 stimulation. Furthermore, TNFR1 activation induced significant MLKL(Ser358) and Drp1(Ser616) phosphorylation, physical interactions in RCC between RIPK1-RIPK3 and RIPK3-phospho-MLKL(Ser358), and coincidence of phospho-MLKL(ser358) and phospho-Drp1(Ser616) at mitochondria in TUNEL-positive RCC. A caspase inhibitor only partially reduced the extent of cell death following TNFR1 engagement in RCC cells, whereas three inhibitors, each targeting a different step in the necroptotic pathway, were much more protective. Combined inhibition of caspases and necroptosis provided additive protection, implying that different subsets of cells respond differently to TNF-α, the majority dying by necroptosis. We conclude that most high-grade RCC cells express increased amounts of RIPK1 and RIPK3 and are poised to undergo necroptosis in response to TNFR1 signaling.

Indexed as

ApoptosisAcrylamidesCarcinoma, Renal CellEpithelial CellsGene Expression Regulation, NeoplasticHumansIn Situ Nick-End LabelingKidney NeoplasmsKidney TubulesNecrosisOrgan Culture TechniquesQuinazolinonesReceptor-Interacting Protein Serine-Threonine KinasesReceptors, Tumor Necrosis Factor, Type IRNA, MessengerSignal Transduction3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinoneAcrylamidesN-(4-(N-(3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophene-2-yl)acrylamideQuinazolinonesReceptor-Interacting Protein Serine-Threonine KinasesReceptors, Tumor Necrosis Factor, Type IRIPK1 protein, humanRIPK3 protein, humanRNA, MessengerSulfonamidesTumor Necrosis Factor-alpha

Identifiers

PMID27362805
PMCPMC5108336
OpenAlexW2468375317

What OpenQuestion holds

Textmetadata
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.