TY - JOUR
T1 - Activated thyroid hormone promotes differentiation and chemotherapeutic sensitization of colorectal cancer stem cells by regulating Wnt and BMP4 signaling
AU - Benfante, Antonina
AU - Stassi, Giorgio
AU - Todaro, Matilde
AU - Carollo, Rosachiara
AU - Luongo, Cristina
AU - Ambrosio, Raffaele
AU - Dentice, Monica
AU - Salvatore, Domenico
AU - Catalano, Veronica
PY - 2016
Y1 - 2016
N2 - 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 druginduced cell differentiation may represent a promising therapy for preventing CSC expansion and tumor progression.
AB - 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 druginduced cell differentiation may represent a promising therapy for preventing CSC expansion and tumor progression.
KW - Animals; Bone Morphogenetic Protein 4; Cell Differentiation; Cell Line
KW - Tumor; Colorectal Neoplasms; Humans; Male; Mice; Middle Aged; Neoplastic Stem Cells; Signal Transduction; Thyroid Hormones; Wnt Signaling Pathway; Cancer Research; Oncology
KW - Animals; Bone Morphogenetic Protein 4; Cell Differentiation; Cell Line
KW - Tumor; Colorectal Neoplasms; Humans; Male; Mice; Middle Aged; Neoplastic Stem Cells; Signal Transduction; Thyroid Hormones; Wnt Signaling Pathway; Cancer Research; Oncology
UR - http://hdl.handle.net/10447/181757
UR - http://cancerres.aacrjournals.org/content/76/5/1237.full.pdf
M3 - Article
VL - 76
SP - 137
EP - 1244
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
ER -