Impact of the thyroid hormone T3 and its nuclear receptor TRα1 on colon cancer stem cell phenotypes and response to chemotherapies.

Autor: Giolito MV; Université de Strasbourg, INSERM, IRFAC/UMR-S1113, FMTS, 67200, Strasbourg, France.; Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Experimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, B1.57.04, B-1200, Brussels, Belgium., Bodoirat S; Université de Strasbourg, INSERM, IRFAC/UMR-S1113, FMTS, 67200, Strasbourg, France., La Rosa T; Stem-Cell and Brain Research Institute, U1208 INSERM, USC1361 INRA, 69675, Bron, France., Reslinger M; Université de Strasbourg, INSERM, IRFAC/UMR-S1113, FMTS, 67200, Strasbourg, France.; Université de Strasbourg, CNRS, INSERM, IGBMC UMR 7104-UMR-S 1258, Illkirch, France., Guardia GDA; Centro de Oncologia Molecular, Hospital Sírio-Libanês, São Paulo, Brazil., Mourtada J; Université de Strasbourg, INSERM, IRFAC/UMR-S1113, FMTS, 67200, Strasbourg, France., Claret L; Université de Strasbourg, INSERM, IRFAC/UMR-S1113, FMTS, 67200, Strasbourg, France.; Université de Strasbourg, CNRS, INSERM, IGBMC UMR 7104-UMR-S 1258, Illkirch, France., Joung A; Université de Strasbourg, INSERM, IRFAC/UMR-S1113, FMTS, 67200, Strasbourg, France.; Laboratoire de Biologie Tumorale, Institut de Cancérologie Strasbourg Europe, Strasbourg, France., Galante PAF; Centro de Oncologia Molecular, Hospital Sírio-Libanês, São Paulo, Brazil., Penalva LOF; Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA., Plateroti M; Université de Strasbourg, INSERM, IRFAC/UMR-S1113, FMTS, 67200, Strasbourg, France. michelina.plateroti@igbmc.fr.; Université de Strasbourg, CNRS, INSERM, IGBMC UMR 7104-UMR-S 1258, Illkirch, France. michelina.plateroti@igbmc.fr.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2024 May 01; Vol. 15 (5), pp. 306. Date of Electronic Publication: 2024 May 01.
DOI: 10.1038/s41419-024-06690-x
Abstrakt: 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 .
(© 2024. The Author(s).)
Databáze: MEDLINE
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