Impact of the thyroid hormone T3 and its nuclear receptor TRα1 on colon cancer stem cell phenotypes and response to chemotherapies.
Humans
Neoplastic Stem Cells
/ metabolism
Fluorouracil
/ pharmacology
Thyroid Hormone Receptors alpha
/ metabolism
Caco-2 Cells
Colonic Neoplasms
/ metabolism
Spheroids, Cellular
/ drug effects
Triiodothyronine
/ pharmacology
Leucovorin
/ pharmacology
Camptothecin
/ pharmacology
Phenotype
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Aldehyde Dehydrogenase 1 Family
/ metabolism
Drug Resistance, Neoplasm
/ drug effects
Retinal Dehydrogenase
/ metabolism
ATP Binding Cassette Transporter, Subfamily G, Member 2
/ metabolism
ATP Binding Cassette Transporter, Subfamily B
/ metabolism
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
01 May 2024
01 May 2024
Historique:
received:
12
11
2023
accepted:
17
04
2024
revised:
14
04
2024
medline:
2
5
2024
pubmed:
2
5
2024
entrez:
1
5
2024
Statut:
epublish
Résumé
Colorectal cancers (CRCs) are highly heterogeneous and show a hierarchical organization, with cancer stem cells (CSCs) responsible for tumor development, maintenance, and drug resistance. Our previous studies showed the importance of thyroid hormone-dependent signaling on intestinal tumor development and progression through action on stem cells. These results have a translational value, given that the thyroid hormone nuclear receptor TRα1 is upregulated in human CRCs, including in the molecular subtypes associated with CSC features. We used an established spheroid model generated from the human colon adenocarcinoma cell line Caco2 to study the effects of T3 and TRα1 on spheroid formation, growth, and response to conventional chemotherapies. Our results show that T3 treatment and/or increased TRα1 expression in spheroids impaired the response to FOLFIRI and conferred a survival advantage. This was achieved by stimulating drug detoxification pathways and increasing ALDH1A1-expressing cells, including CSCs, within spheroids. These results suggest that clinical evaluation of the thyroid axis and assessing TRα1 levels in CRCs could help to select optimal therapeutic regimens for patients with CRC. Proposed mechanism of action of T3/TRα1 in colon cancer spheroids. In the control condition, TRα1 participates in maintaining homeostatic cell conditions. The presence of T3 in the culture medium activates TRα1 action on target genes, including the drug efflux pumps ABCG2 and ABCB1. In the case of chemotherapy FOLFIRI, the increased expression of ABC transcripts and proteins induced by T3 treatment is responsible for the augmented efflux of 5-FU and Irinotecan from the cancer cells. Taken together, these mechanisms contribute to the decreased efficacy of the chemotherapy and allow cells to escape the treatment. Created with BioRender.com .
Identifiants
pubmed: 38693105
doi: 10.1038/s41419-024-06690-x
pii: 10.1038/s41419-024-06690-x
doi:
Substances chimiques
Fluorouracil
U3P01618RT
Thyroid Hormone Receptors alpha
0
Triiodothyronine
06LU7C9H1V
Leucovorin
Q573I9DVLP
Camptothecin
XT3Z54Z28A
Aldehyde Dehydrogenase 1 Family
EC 1.2.1
Retinal Dehydrogenase
EC 1.2.1.36
ALDH1A1 protein, human
EC 1.2.1.36
ATP Binding Cassette Transporter, Subfamily G, Member 2
0
ATP Binding Cassette Transporter, Subfamily B
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
306Subventions
Organisme : Fondation pour la Recherche Médicale (Foundation for Medical Research in France)
ID : DEQ20181039598
Organisme : Institut National Du Cancer (French National Cancer Institute)
ID : PLBIO19-289
Organisme : Ligue Contre le Cancer
ID : 01X.2021
Informations de copyright
© 2024. The Author(s).
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