An ARC-Regulated IL1β/Cox-2/PGE2/β-Catenin/ARC Circuit Controls Leukemia-Microenvironment Interactions and Confers Drug Resistance in AML.
Animals
Apoptosis
Biomarkers, Tumor
/ metabolism
Cell Proliferation
Cyclooxygenase 2
/ genetics
Cytoskeletal Proteins
/ pharmacology
Dinoprostone
/ pharmacology
Drug Resistance, Neoplasm
Female
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Interleukin-1beta
/ genetics
Leukemia, Myeloid, Acute
/ drug therapy
Male
Mesenchymal Stem Cells
/ drug effects
Mice
Mice, Inbred NOD
Mice, SCID
Nerve Tissue Proteins
/ pharmacology
Oxytocics
/ pharmacology
Tumor Cells, Cultured
Tumor Microenvironment
Xenograft Model Antitumor Assays
beta Catenin
/ genetics
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
15 03 2019
15 03 2019
Historique:
received:
26
03
2018
revised:
17
09
2018
accepted:
16
01
2019
pubmed:
25
1
2019
medline:
19
12
2019
entrez:
25
1
2019
Statut:
ppublish
Résumé
The apoptosis repressor with caspase recruitment domain (ARC) protein is a strong independent adverse prognostic marker in acute myeloid leukemia (AML). We previously reported that ARC regulates leukemia-microenvironment interactions through the NFκB/IL1β signaling network. Malignant cells have been reported to release IL1β, which induces PGE2 synthesis in mesenchymal stromal cells (MSC), in turn activating β-catenin signaling and inducing the cancer stem cell phenotype. Although Cox-2 and its enzymatic product PGE2 play major roles in inflammation and cancer, the regulation and role of PGE2 in AML are largely unknown. Here, we report that AML-MSC cocultures greatly increase Cox-2 expression in MSC and PGE2 production in an ARC/IL1β-dependent manner. PGE2 induced the expression of β-catenin, which regulated ARC and augmented chemoresistance in AML cells; inhibition of β-catenin decreased ARC and sensitized AML cells to chemotherapy. NOD/SCIDIL2RγNull-3/GM/SF mice transplanted with ARC-knockdown AML cells had significantly lower leukemia burden, lower serum levels of IL1β/PGE2, and lower tissue human ARC and β-catenin levels, prolonged survival, and increased sensitivity to chemotherapy than controls. Collectively, we present a new mechanism of action of antiapoptotic ARC by which ARC regulates PGE2 production in the tumor microenvironment and microenvironment-mediated chemoresistance in AML.
Identifiants
pubmed: 30674535
pii: 0008-5472.CAN-18-0921
doi: 10.1158/0008-5472.CAN-18-0921
pmc: PMC6420856
mid: NIHMS1519477
doi:
Substances chimiques
Biomarkers, Tumor
0
CTNNB1 protein, human
0
Cytoskeletal Proteins
0
IL1B protein, human
0
Interleukin-1beta
0
Nerve Tissue Proteins
0
Oxytocics
0
activity regulated cytoskeletal-associated protein
0
beta Catenin
0
Cyclooxygenase 2
EC 1.14.99.1
PTGS2 protein, human
EC 1.14.99.1
Dinoprostone
K7Q1JQR04M
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1165-1177Subventions
Organisme : NCI NIH HHS
ID : P01 CA055164
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Informations de copyright
©2019 American Association for Cancer Research.
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