Molecular pathways involved in the antineoplastic effects of calcitriol on insulinoma cells

Francesca Galbiati, Luca Polastri, Bernard Thorens, Philippe Dupraz, Paolo Fiorina, Ugo Cavallaro, Gerhard Christofori, Alberto M. Davalli

Research output: Contribution to journalArticlepeer-review

Abstract

We have previously reported that in tumorigenic pancreatic β-cells, calcitriol exerts a potent antitumorigenic effect by inducing apoptosis, cell growth inhibition, and reduction of solid β-cell tumors. Here we have studied the molecular pathways involved in the antineoplastic activity of calcitriol on mouse insulinoma βTC3 cells, mouse insulinoma βTC expressing or not expressing the oncogene p53, and βTC-tet cells overexpressing or not the antiapoptotic gene Bcl2. Our results indicate that calcitriol-induced apoptosis was dependent on the function of p53 and was associated with a biphasic increase in protein levels of transcription factor nuclear factor-κB. Calcitriol decreased cell viability by about 40% in p53-retaining βTC and in βTC3 cells; in contrast, βTC p53-/- cells were only minimally affected. Calcitriol-induced cell death was regulated by members of the Bcl-2 family of apoptosis regulatory proteins, as shown by calcitriol-induced up-regulation of proapoptotic Bax and Bak and the lack of calcitriol-induced cytotoxicity in Bcl-2-overexpressing insulinoma cells. Moreover, calcitriol-mediated arrest of βTC3 cells in the G1 phase of the cell cycle was associated with the abnormal expression of p21 and G2/M-specific cyclin B2 genes and involved the DNA damage-inducible factor GADD45. Finally, in βTC3 cells, calcitriol modulated the expression of IGF-I and IGF-II genes. In conclusion, these findings contribute to the understanding of the antitumorigenic effects of calcitriol on tumorigenic pancreatic β-cells and further support the rationale of its utilization in the treatment of patients with malignant insulinomas.

Original languageEnglish
Pages (from-to)1832-1841
Number of pages10
JournalEndocrinology
Volume144
Issue number5
DOIs
Publication statusPublished - May 1 2003

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

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