Evidence map›Paper›PMID 28154014›Full record

ArticleThe Journal of pharmacology and experimental therapeutics2017

A Tumor Cell-Selective Inhibitor of Mitogen-Activated Protein Kinase Phosphatases Sensitizes Breast Cancer Cells to Lymphokine-Activated Killer Cell Activity.

Christof T Kaltenmeier, Laura L Vollmer, Lawrence A Vernetti, Lindsay Caprio, Keanu Davis, Vasiliy N Korotchenko, Billy W Day, Michael Tsang, Keren I Hulkower, Michael T Lotze and 1 more

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

Article in The Journal of pharmacology and experimental therapeutics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.

0numbers the graph read from it
0cells of the map it votes in
22citing papers in PubMed
2.4field-weighted citation impact, top 11% 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

22 citing papers in PubMed, 40 citations in OpenAlex.

  1. Review
  2. Article
  3. Article
  4. Review
  5. Article
  6. Article
  7. Article
  8. Dual-specificity phosphatases: therapeutic targets in cancer therapy resistance.Journal of cancer research and clinical oncology · 2022
    Review
  9. Article
  10. Targeting Phosphatases and Kinases: How to Checkmate Cancer.Frontiers in cell and developmental biology · 2021
    Review
  11. Review
  12. Targeted Inhibition of the Dual Specificity Phosphatases DUSP1 and DUSP6 Suppress MPNST Growth via JNK.Clinical cancer research : an official journal of the American Association for Cancer Research · 2019
    Article
  13. Article
  14. Review
  15. Article
  16. Review
  17. Article
  18. Hirudin Protects Ang II-Induced Myocardial Fibroblasts Fibrosis by Inhibiting the Extracellular Signal-Regulated Kinase1/2 (ERK1/2) Pathway.Medical science monitor : international medical journal of experimental and clinical research · 2018
    Article
  19. Article
  20. Review
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

11 authors at 3 institutions in 1 country.

Christof T KaltenmeierDepartments of Surgery, Immunology and Biochemistry (C.T.K., M.T.L.), Drug Discovery Institute (L.L.V., L.A.V., L.C., K.D., M.T.L., A.V.), Department of Computational and Systems Biology (L.A.V., A.V.), Department of Pharmaceutical Sciences (V.N.K., B.W.D.), and Department of Developmental Biology (M.T.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Platypus Technologies, LLC, Madison, Wisconsin (K.I.H.).
Laura L VollmerDepartments of Surgery, Immunology and Biochemistry (C.T.K., M.T.L.), Drug Discovery Institute (L.L.V., L.A.V., L.C., K.D., M.T.L., A.V.), Department of Computational and Systems Biology (L.A.V., A.V.), Department of Pharmaceutical Sciences (V.N.K., B.W.D.), and Department of Developmental Biology (M.T.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Platypus Technologies, LLC, Madison, Wisconsin (K.I.H.).
Lawrence A VernettiDepartments of Surgery, Immunology and Biochemistry (C.T.K., M.T.L.), Drug Discovery Institute (L.L.V., L.A.V., L.C., K.D., M.T.L., A.V.), Department of Computational and Systems Biology (L.A.V., A.V.), Department of Pharmaceutical Sciences (V.N.K., B.W.D.), and Department of Developmental Biology (M.T.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Platypus Technologies, LLC, Madison, Wisconsin (K.I.H.).
Lindsay CaprioDepartments of Surgery, Immunology and Biochemistry (C.T.K., M.T.L.), Drug Discovery Institute (L.L.V., L.A.V., L.C., K.D., M.T.L., A.V.), Department of Computational and Systems Biology (L.A.V., A.V.), Department of Pharmaceutical Sciences (V.N.K., B.W.D.), and Department of Developmental Biology (M.T.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Platypus Technologies, LLC, Madison, Wisconsin (K.I.H.).
Keanu DavisDepartments of Surgery, Immunology and Biochemistry (C.T.K., M.T.L.), Drug Discovery Institute (L.L.V., L.A.V., L.C., K.D., M.T.L., A.V.), Department of Computational and Systems Biology (L.A.V., A.V.), Department of Pharmaceutical Sciences (V.N.K., B.W.D.), and Department of Developmental Biology (M.T.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Platypus Technologies, LLC, Madison, Wisconsin (K.I.H.).
Vasiliy N KorotchenkoDepartments of Surgery, Immunology and Biochemistry (C.T.K., M.T.L.), Drug Discovery Institute (L.L.V., L.A.V., L.C., K.D., M.T.L., A.V.), Department of Computational and Systems Biology (L.A.V., A.V.), Department of Pharmaceutical Sciences (V.N.K., B.W.D.), and Department of Developmental Biology (M.T.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Platypus Technologies, LLC, Madison, Wisconsin (K.I.H.).
Billy W DayDepartments of Surgery, Immunology and Biochemistry (C.T.K., M.T.L.), Drug Discovery Institute (L.L.V., L.A.V., L.C., K.D., M.T.L., A.V.), Department of Computational and Systems Biology (L.A.V., A.V.), Department of Pharmaceutical Sciences (V.N.K., B.W.D.), and Department of Developmental Biology (M.T.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Platypus Technologies, LLC, Madison, Wisconsin (K.I.H.).
Michael TsangDepartments of Surgery, Immunology and Biochemistry (C.T.K., M.T.L.), Drug Discovery Institute (L.L.V., L.A.V., L.C., K.D., M.T.L., A.V.), Department of Computational and Systems Biology (L.A.V., A.V.), Department of Pharmaceutical Sciences (V.N.K., B.W.D.), and Department of Developmental Biology (M.T.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Platypus Technologies, LLC, Madison, Wisconsin (K.I.H.).
Keren I HulkowerDepartments of Surgery, Immunology and Biochemistry (C.T.K., M.T.L.), Drug Discovery Institute (L.L.V., L.A.V., L.C., K.D., M.T.L., A.V.), Department of Computational and Systems Biology (L.A.V., A.V.), Department of Pharmaceutical Sciences (V.N.K., B.W.D.), and Department of Developmental Biology (M.T.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Platypus Technologies, LLC, Madison, Wisconsin (K.I.H.).
Michael T LotzeDepartments of Surgery, Immunology and Biochemistry (C.T.K., M.T.L.), Drug Discovery Institute (L.L.V., L.A.V., L.C., K.D., M.T.L., A.V.), Department of Computational and Systems Biology (L.A.V., A.V.), Department of Pharmaceutical Sciences (V.N.K., B.W.D.), and Department of Developmental Biology (M.T.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Platypus Technologies, LLC, Madison, Wisconsin (K.I.H.).
Andreas VogtDepartments of Surgery, Immunology and Biochemistry (C.T.K., M.T.L.), Drug Discovery Institute (L.L.V., L.A.V., L.C., K.D., M.T.L., A.V.), Department of Computational and Systems Biology (L.A.V., A.V.), Department of Pharmaceutical Sciences (V.N.K., B.W.D.), and Department of Developmental Biology (M.T.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Platypus Technologies, LLC, Madison, Wisconsin (K.I.H.) avogt@pitt.edu.
Discovery Institute · USL-3 Communications (United States) · USUniversity of Pittsburgh · US

Funding

VECTOR CORE FACILITYP30CA047904 · NCI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI JOHN C. BYRD · 1988 to 2026
$158.0M
Utilizing Small Molecule Screens to Delineate Embryonic Signaling MechanismsR01HD053287 · NICHD · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI HUKRIEDE, NEIL A, TSANG, MICHAEL WAIKOK · 2007 to 2016
$3.1M
Pancreatic Ductal Adenocarcinoma is a disease of constitutive autophagyR01CA181450 · NCI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI LOTZE, MICHAEL T, ZEH, HERBERT J · 2014 to 2018
$1.6M
Transformative HTS cell migration assay for rapid screening of cancer therapeuticR21CA147985 · NCI · PLATYPUS TECHNOLOGIES, LLC · PI ACHARYA, BHARAT R, VOGT, ANDREAS · 2010 to 2011
$336k
NCI NIH HHS P30 CA047904NCI NIH HHS R01 CA181450NCI NIH HHS R21 CA147985NICHD NIH HHS R01 HD053287
6 · The paper itself

Abstract

Dual specificity mitogen-activated protein kinase (MAPK) phosphatases [dual specificity phosphatase/MAP kinase phosphatase (DUSP-MKP)] have been hypothesized to maintain cancer cell survival by buffering excessive MAPK signaling caused by upstream activating oncogenic products. A large and diverse body of literature suggests that genetic depletion of DUSP-MKPs can reduce tumorigenicity, suggesting that hyperactivating MAPK signaling by DUSP-MKP inhibitors could be a novel strategy to selectively affect the transformed phenotype. Through in vivo structure-activity relationship studies in transgenic zebrafish we recently identified a hyperactivator of fibroblast growth factor signaling [(E)-2-benzylidene-5-bromo-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI-215)] that is devoid of developmental toxicity and restores defective MAPK activity caused by overexpression of DUSP1 and DUSP6 in mammalian cells. Here, we hypothesized that BCI-215 could selectively affect survival of transformed cells. In MDA-MB-231 human breast cancer cells, BCI-215 inhibited cell motility, caused apoptosis but not primary necrosis, and sensitized cells to lymphokine-activated killer cell activity. Mechanistically, BCI-215 induced rapid and sustained phosphorylation of extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK) in the absence of reactive oxygen species, and its toxicity was partially rescued by inhibition of p38 but not JNK or ERK. BCI-215 also hyperactivated MKK4/SEK1, suggesting activation of stress responses. Kinase phosphorylation profiling documented BCI-215 selectively activated MAPKs and their downstream substrates, but not receptor tyrosine kinases, SRC family kinases, AKT, mTOR, or DNA damage pathways. Our findings support the hypothesis that BCI-215 causes selective cancer cell cytotoxicity in part through non-redox-mediated activation of MAPK signaling, and the findings also identify an intersection with immune cell killing that is worthy of further exploration.

Indexed as

AnimalsAnimals, Genetically ModifiedAntineoplastic AgentsBreast NeoplasmsDose-Response Relationship, DrugEnzyme InhibitorsFemaleHeLa CellsHepatocytesHumansJNK Mitogen-Activated Protein KinasesKiller Cells, Lymphokine-ActivatedMitogen-Activated Protein Kinase PhosphatasesRatsZebrafishAntineoplastic AgentsEnzyme InhibitorsJNK Mitogen-Activated Protein KinasesMitogen-Activated Protein Kinase Phosphatases

Identifiers

PMID28154014
PMCPMC5363763
OpenAlexW2585972588

What OpenQuestion holds

Textmetadata
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.