This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Galbiati, F. Articles by Davalli, A. M. Search for Related Content PubMed PubMed Citation Articles by Galbiati, F. Articles by Davalli, A. M.

Molecular Pathways Involved in the Antineoplastic Effects of Calcitriol on Insulinoma Cells

Division of General Medicine, Unit of Endocrinology and Metabolic Disease, San Raffaele Scientific Institute (F.G., L.P., P.F., A.M.D.), 20132 Milan, Italy; Institute of Pharmacology, University of Lausanne (B.T., P.D.), CH-1005 Lausanne, Switzerland; and Institute of Biochemistry and Genetics, University of Basel (U.C., G.C.), CH-4051 Basel, Switzerland

Address all correspondence and requests for reprints to: Dr. Alberto M. Davalli, Division of General Medicine, Unit of Endocrinology and Metabolic Disease, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy. E-mail: alberto.davalli{at}hsr.it.

We have previously reported that in tumorigenic pancreatic ß-cells, calcitriol exerts a potent antitumorigenic effect by inducing apoptosis, cell growth inhibition, and reduction of solid ß-cell tumors. Here we have studied the molecular pathways involved in the antineoplastic activity of calcitriol on mouse insulinoma ßTC₃ cells, mouse insulinoma ßTC expressing or not expressing the oncogene p53, and ßTC-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-B. Calcitriol decreased cell viability by about 40% in p53-retaining ßTC and in ßTC₃ cells; in contrast, ßTC 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 ßTC₃ 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 ßTC₃ 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 ß-cells and further support the rationale of its utilization in the treatment of patients with malignant insulinomas.

This article has been cited by other articles:

				M. F. McCarty and K. I. Block Preadministration of High-Dose Salicylates, Suppressors of NF-{kappa}B Activation, May Increase the Chemosensitivity of Many Cancers: An Example of Proapoptotic Signal Modulation Therapy. Integr Cancer Ther, September 1, 2006; 5(3): 252 - 268. [Abstract] [PDF]

				C. Crescioli, A. Morelli, L. Adorini, P. Ferruzzi, M. Luconi, G. B. Vannelli, M. Marini, S. Gelmini, B. Fibbi, S. Donati, et al. Human Bladder as a Novel Target for Vitamin D Receptor Ligands J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 962 - 972. [Abstract] [Full Text] [PDF]

				A. P. B. Dackiw, S. Ezzat, P. Huang, W. Liu, and S. L. Asa Vitamin D3 Administration Induces Nuclear p27 Accumulation, Restores Differentiation, and Reduces Tumor Burden in a Mouse Model of Metastatic Follicular Thyroid Cancer Endocrinology, December 1, 2004; 145(12): 5840 - 5846. [Abstract] [Full Text] [PDF]