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

Abstract

We have previously reported that in tumorigenic pancreatic beta-cells, calcitriol exerts a potent antitumorigenic effect by inducing apoptosis, cell growth inhibition, and reduction of solid beta-cell tumors. Here we have studied the molecular pathways involved in the antineoplastic activity of calcitriol on mouse insulinoma beta TC(3) cells, mouse insulinoma beta TC expressing or not expressing the oncogene p53, and beta TC-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-kappa B. Calcitriol decreased cell viability by about 40% in p53-retaining beta TC and in beta TC(3) cells; in contrast, beta TC 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 beta TC(3) cells in the G(1) phase of the cell cycle was associated with the abnormal expression of p21 and G(2)/M-specific cyclin B2 genes and involved the DNA damage-inducible factor GADD45. Finally, in beta TC(3) 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 beta-cells and further support the rationale of its utilization in the treatment of patients with malignant insulinomas.

Molecular pathways involved in the anti‐apoptotic effect of 1,25‐dihydroxyvitamin D3 in primary human keratinocytes

“…1,25(OH) 2 D 3 has also been identified to influence other Bcl-2 members in a variety of cell types [Wang and Studzinski, 1997;Diaz et al, 2000;Guzey et al, 2002;Galbiati et al, 2003]. Moreover, in addition to upregulating Bcl-2, we showed that 1,25(OH) 2 D 3 suppresses the levels of the proapoptotic proteins Bax and Bad.…”

“…In breast cancer [Narvaez and Welsh, 2001], colon cancer [Diaz et al, 2000], prostate cancer [Guzey et al, 2002], and other cancer cell lines [McGuire et al, 2001;Galbiati et al, 2003;Wagner et al, 2003], 1,25(OH) 2 D 3 has been shown to induce apoptotic cell death. In these cancers, the activation of apoptotic pathways has been implicated as an additional mechanism underlying 1,25(OH) 2 D 3 -mediated growth suppression.…”

IGF2 and cancer

“…Tumour gene therapies targeted at cells expressing IGF2 are another exciting recent development (Amit & Hochberg 2010, Pan et al 2010. Vitamins C and D reduce IGF2 production and IGF1R signalling (Oh et al 2001, Galbiati et al 2003, Lee et al 2008. There may be a place for combining these vitamins, or analogues thereof with other treatments.…”

A20 gene expression is regulated by TNF, Vitamin D and androgen in prostate cancer cells

“…It was shown that A20 expression was regulated at the transcriptional level through B elements in the promoter region of the A20 gene [24]. The ability of Vitamin D to regulate the activity of NF-B has been demonstrated in human fibroblasts [25], human leukaemia [26][27][28] and insulinoma cells [29]. The effects of Vitamin D varied and appear to be cell specific.…”