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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)137-1244
Number of pages1108
JournalCancer Research
Volume76
Issue number5
DOIs
Publication statusPublished - Mar 1 2016

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Fingerprint Dive into the research topics of 'Activated thyroid hormone promotes differentiation and chemotherapeutic sensitization of colorectal cancer stem cells by regulating Wnt and BMP4 signaling'. Together they form a unique fingerprint.

Cite this