Wnt/IL-1β/IL-8 autocrine circuitries control chemoresistance in mesothelioma initiating cells by inducing ABCB5.
ATP Binding Cassette Transporter, Subfamily B
/ genetics
Animals
Antineoplastic Agents
/ therapeutic use
Cell Line, Tumor
Drug Resistance, Neoplasm
/ genetics
Female
Humans
Interleukin-1beta
/ metabolism
Interleukin-8
/ metabolism
Mesothelioma
/ drug therapy
Mice
Mice, Inbred BALB C
Mice, Knockout
Pleural Neoplasms
/ drug therapy
Wnt Signaling Pathway
ABCB5
chemoresistance
initiating cells
malignant pleural mesothelioma
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
01 01 2020
01 01 2020
Historique:
received:
02
12
2018
revised:
10
05
2019
accepted:
15
05
2019
pubmed:
21
5
2019
medline:
15
2
2020
entrez:
21
5
2019
Statut:
ppublish
Résumé
Malignant pleural mesothelioma (MPM) is a tumor with high chemoresistance and poor prognosis. MPM-initiating cells (ICs) are known to be drug resistant, but it is unknown if and how stemness-related pathways determine chemoresistance. Moreover, there are no predictive markers of IC-associated chemoresistance. Aim of this work is to clarify if and by which mechanisms the chemoresistant phenotype of MPM IC was due to specific stemness-related pathways. We generated MPM IC from primary MPM samples and compared the gene expression and chemo-sensitivity profile of IC and differentiated/adherent cells (AC) of the same patient. Compared to AC, IC had upregulated the drug efflux transporter ABCB5 that determined resistance to cisplatin and pemetrexed. ABCB5-knocked-out (KO) IC clones were resensitized to the drugs in vitro and in patient-derived xenografts. ABCB5 was transcriptionally activated by the Wnt/GSK3β/β-catenin/c-myc axis that also increased IL-8 and IL-1β production. IL-8 and IL-1β-KO IC clones reduced the c-myc-driven transcription of ABCB5 and reacquired chemosensitivity. ABCB5-KO clones had lower IL-8 and IL-1β secretion, and c-myc transcriptional activity, suggesting that either Wnt/GSK3β/β-catenin and IL-8/IL-1β signaling drive c-myc-mediated transcription of ABCB5. ABCB5 correlated with lower time-to-progression and overall survival in MPM patients treated with cisplatin and pemetrexed. Our work identified multiple autocrine loops linking stemness pathways and resistance to cisplatin and pemetrexed in MPM IC. ABCB5 may represent a new target to chemosensitize MPM IC and a potential biomarker to predict the response to the first-line chemotherapy in MPM patients.
Substances chimiques
ABCB5 protein, human
0
ATP Binding Cassette Transporter, Subfamily B
0
Antineoplastic Agents
0
CXCL8 protein, human
0
IL1B protein, human
0
Interleukin-1beta
0
Interleukin-8
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
192-207Informations de copyright
© 2019 UICC.
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