Activated thyroid hormone promotes differentiation and chemotherapeutic sensitization of colorectal cancer stem cells by regulating Wnt and BMP4 signaling

Giorgio Stassi, Antonina Benfante, Rosachiara Carollo, Matilde Todaro, Cristina Luongo, Raffaele Ambrosio, Monica Dentice, Domenico Salvatore, Veronica Catalano

Risultato della ricerca: Article

36 Citazioni (Scopus)

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 druginduced cell differentiation may represent a promising therapy for preventing CSC expansion and tumor progression.
Lingua originaleEnglish
pagine (da-a)137-1244
Numero di pagine1108
RivistaCancer Research
Volume76
Stato di pubblicazionePublished - 2016

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All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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