title: Activated Thyroid Hormone Promotes Differentiation and Chemotherapeutic Sensitization of Colorectal Cancer Stem Cells by Regulating Wnt and BMP4 Signaling.
abstract: Thyroid hormone is a pleiotropic factor that controls many cellular processes in multiple cell types such as cancer stem cells (CSC). Thyroid hormone concentrations in the blood are stable, but the action of the deiodinases (D2-D3) provides cell-specific regulation of thyroid hormone activity. Deregulation of deiodinase function and thyroid hormone status has been implicated in tumorigenesis. Therefore, we investigated the role of thyroid hormone metabolism and signaling in colorectal CSCs (CR-CSC), where deiodinases control cell division and chemosensitivity. We found that increased intracellular thyroid hormone concentration through D3 depletion induced cell differentiation and sharply mitigated tumor formation. Upregulated BMP4 expression and concomitantly attenuated Wnt signaling accompanied these effects. Furthermore, we demonstrate that BMP4 is a direct thyroid hormone target and is involved in a positive autoregulatory feedback loop that modulates thyroid hormone signaling. Collectively, our findings highlight a cell-autonomous metabolic mechanism by which CR-CSCs exploit thyroid hormone signaling to facilitate their self-renewal potential and suggest that drug-induced cell differentiation may represent a promising therapy for preventing CSC expansion and tumor progression.
authors.affiliation: Surgical and Oncological Sciences, University of Palermo, Palermo, Italy. Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), University of Palermo, Palermo, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Catalano
authors.affiliation: Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Dentice
authors.affiliation: IRCCS SDN, Naples, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Ambrosio
authors.affiliation: Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Luongo
authors.affiliation: Surgical and Oncological Sciences, University of Palermo, Palermo, Italy.
authors.forename: Rosachiara
authors.initials: R
authors.lastname: Carollo
authors.affiliation: Surgical and Oncological Sciences, University of Palermo, Palermo, Italy.
authors.forename: Antonina
authors.initials: A
authors.lastname: Benfante
authors.affiliation: Surgical and Oncological Sciences, University of Palermo, Palermo, Italy. Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), University of Palermo, Palermo, Italy.
authors.forename: Matilde
authors.initials: M
authors.lastname: Todaro
authors.affiliation: Surgical and Oncological Sciences, University of Palermo, Palermo, Italy. domsalva@unina.it giorgio.stassi@unipa.it.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Stassi
authors.affiliation: Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy. CEINGE-Biotecnologie Avanzate, Naples, Italy. domsalva@unina.it giorgio.stassi@unipa.it.
authors.forename: Domenico
authors.initials: D
authors.lastname: Salvatore
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects*; D015398:Signal Transduction / Q000502:physiology*; D013963:Thyroid Hormones / Q000502:physiology*; D060449:Wnt Signaling Pathway / Q000502:physiology*
chemical_list: C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D013963:Thyroid Hormones