Evidence map›Paper›PMID 25179733›Full record

ArticleLeukemia2015

Targeting phospho-MARCKS overcomes drug-resistance and induces antitumor activity in preclinical models of multiple myeloma.

Y Yang, Y Chen, M N Saha, J Chen, K Evans, L Qiu, D Reece, G A Chen, H Chang

Abstract read
PubMed Publisher
In one paragraph

Article in Leukemia, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
48citing papers in PubMed, 1 pooled it
4.1field-weighted citation impact, top 6% 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

48 citing papers in PubMed, 1 synthesis or guideline pooled it, 76 citations in OpenAlex.

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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

9 authors at 4 institutions in 2 countries.

Y Yang1] Division of Molecular and Cellular Biology, Toronto General Research Institute, Toronto, Canada [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
Y Chen1] Division of Molecular and Cellular Biology, Toronto General Research Institute, Toronto, Canada [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada [3] Department of Hematology/Oncology, First Affiliated Hospital, Nanchang University, Nanchang, China.
M N Saha1] Division of Molecular and Cellular Biology, Toronto General Research Institute, Toronto, Canada [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
J ChenOntario Cancer Biomarker Network, Toronto, Canada.
K EvansOntario Cancer Biomarker Network, Toronto, Canada.
L QiuDepartment of Lymphoma & Myeloma, Institute of Hematology & Blood Diseases Hospital, State Key Laboratory of Experimental Hematology, Chinese Academy of Medical Sciences & Peking Union of Medical College, Tianjin, People's Republic of China.
D ReeceDepartment of Laboratory Hematology and Medical Oncology, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.
G A ChenDepartment of Hematology/Oncology, First Affiliated Hospital, Nanchang University, Nanchang, China.
H Chang1] Division of Molecular and Cellular Biology, Toronto General Research Institute, Toronto, Canada [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada [3] Department of Hematology/Oncology, First Affiliated Hospital, Nanchang University, Nanchang, China [4] Department of Laboratory Hematology and Medical Oncology, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.
Toronto General Hospital · CAInstitute of Hematology & Blood Diseases Hospital · CNNanchang University · CNUniversity of Toronto · CA

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Multiple myeloma (MM) is incurable in virtually all patients due to the presence of innate and emergent drug-resistance. To identify potential drug resistance mechanisms in MM we used iTRAQ (isobaric tags for relative and absolute quantitation) mass spectrometry to compare protein expression profiles of drug-resistant (RPMI 8226-R5) and sensitive (RPMI 8226-S) isogenic cell lines. We identified selective overexpression of myristoylated alanine-rich C-kinase substrate (MARCKS) in drug-resistant R5 cells. MARCKS overexpression was also observed in several drug-resistant human myeloma cell lines (HMCLs) and in drug-resistant primary MM samples. Functionally, inhibition of MARCKS phosphorylation by enzastaurin or knockdown of the gene by RNAi significantly enhanced the sensitivity of resistant HMCLs and primary MM samples to bortezomib and to other anti-myeloma drugs, providing evidence that MARCKS can modulate drug response. Mechanistically, pMARCKS (phosphorylated form of MARCKS) was found to function as an E2F-1 cofactor to regulate SKP2 transcription. pMARCKS promoted cell-cycle progression by facilitating SKP2 expression, suppressing p27(Kip1) and potentially counteracting drug-induced cell-cycle arrest by promoting Cyclin E/CDK2 activity. Importantly, MARCKS knockdown in combination with bortezomib treatment overcame bortezomib resistance, significantly inhibited tumor growth and prolonged host survival in a MM xenograft model. These data provide a rationale for therapeutic targeting of pMARCKS to improve the outcome of patients with refractory/relapsed MM.

Indexed as

Gene Expression Regulation, NeoplasticAnimalsAntineoplastic AgentsBoronic AcidsBortezomibCell CycleCell Line, TumorCyclin-Dependent Kinase 2Cyclin-Dependent Kinase Inhibitor p27Cyclin EDisease Models, AnimalDrug Resistance, NeoplasmE2F1 Transcription FactorHumansIndolesIntracellular Signaling Peptides and ProteinsAntineoplastic AgentsBoronic AcidsBortezomibCdk2 protein, mouseCdkn1b protein, mouseCyclin-Dependent Kinase 2Cyclin-Dependent Kinase Inhibitor p27Cyclin EE2f1 protein, mouseE2F1 Transcription FactorenzastaurinIndolesIntracellular Signaling Peptides and ProteinsMARCKS protein, humanMarcks protein, mouseMembrane ProteinsMyristoylated Alanine-Rich C Kinase SubstratePyrazinesRNA, Small InterferingS-Phase Kinase-Associated Proteins

Identifiers

PMID25179733
OpenAlexW2034266037

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.