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

• Published in: Cell death & disease Vol. 15; no. 5; p. 306
• Main Authors: Giolito, Maria Virginia, Bodoirat, Serguei, La Rosa, Theo, Reslinger, Mathieu, Guardia, Gabriela D. A., Mourtada, Jana, Claret, Leo, Joung, Alain, Galante, Pedro A. F., Penalva, Luiz O. F., Plateroti, Michelina
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-05-2024; Springer Nature B.V; Nature Publishing Group
• Subjects: 13; 13/51; 38; 45; 631/67/1504; 631/67/70; 631/67/71; Adenocarcinoma; Aldehyde Dehydrogenase 1 Family - genetics; Aldehyde Dehydrogenase 1 Family - metabolism; Antibodies; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; ATP Binding Cassette Transporter, Subfamily B - genetics; ATP Binding Cassette Transporter, Subfamily B - metabolism; ATP Binding Cassette Transporter, Subfamily G, Member 2 - genetics; ATP Binding Cassette Transporter, Subfamily G, Member 2 - metabolism; Biochemistry; Biomedical and Life Sciences; Caco-2 Cells; Camptothecin - analogs & derivatives; Camptothecin - pharmacology; Camptothecin - therapeutic use; Cell Biology; Cell Culture; Chemotherapy; Colon cancer; Colonic Neoplasms - drug therapy; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colorectal cancer; Detoxification; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Fluorouracil - pharmacology; Fluorouracil - therapeutic use; Humans; Immunology; Leucovorin - pharmacology; Leucovorin - therapeutic use; Life Sciences; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Phenotype; Phenotypes; Retinal Dehydrogenase - genetics; Retinal Dehydrogenase - metabolism; Spheroids; Spheroids, Cellular - drug effects; Spheroids, Cellular - metabolism; Spheroids, Cellular - pathology; Stem cells; Thyroid gland; Thyroid Hormone Receptors alpha - genetics; Thyroid Hormone Receptors alpha - metabolism; Triiodothyronine; Triiodothyronine - pharmacology; Tumors
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-024-06690-x

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
.