1 , 25-dihydroxyvitamin D3 suppresses interleukin-8-mediated prostate cancer cell angiogenesis

Abstract

Angiogenesis is an essential step in initial tumor development and metastasis. Consequently, compounds that inhibit angiogenesis would be useful in treating cancer. A variety of antitumor effects mediated by 1alpha, 25-dihydroxyvitamin D3 (1,25-VD) have been reported, one of which is anti-angiogenesis; however, detailed mechanisms remain unclear. We have demonstrated that 1,25-VD inhibits prostate cancer (PCa) cell-induced human umbilical vein endothelial cell migration and tube formation, two critical steps involved in the angiogenesis. An angiogenesis factor, interleukin-8 (IL-8), secreted from PCa cell was suppressed by 1,25-VD at both mRNA and protein levels. Mechanistic dissection found that 1,25-VD inhibits NF-kappaB signal, one of the most important IL-8 upstream regulators. The 1,25-VD-mediated NF-kappaB signal reduction was shown to result from the blocking of nuclear translocation of p65, a subunit of the NF-kappaB complex, and was followed by attenuation of the NF-kappaB complex binding to DNA. The role of IL-8 in PCa progression was further examined by PCa tissue microarray analyses. We found that IL-8 expression was elevated during PCa progression, which suggests that IL-8 may play a role in tumor progression mediated through its stimulation on angiogenesis. These findings indicate that 1,25-VD could prevent PCa progression by interrupting IL-8 signaling, which is required in tumor angiogenesis, and thus applying vitamin D in PCa treatment may be beneficial for controlling disease progression.

Oral supplementation with 25(OH)D3 versus vitamin D3: Effects on 25(OH)D levels, lower extremity function, blood pressure, and markers of innate immunity

“…(34,47) 1,25-dihydroxyvitamin D treatment of cancer cells suppressed IL-8 production, which is an angiogenesis factor critical in initial tumor and metastasis development. (48) Further, 1,25-dihydroxyvitamin D treatment inhibited RANTES and IP-10 secretion in a concentration-dependent manner in airway smooth muscle cells. (49) Both chemokines play a critical role in the pathogenesis of asthma, (50) as do eosinophils, which are recruited to the lungs by eotaxin.…”

Molecular pathways mediating the anti-inflammatory effects of calcitriol: implications for prostate cancer chemoprevention and treatment

“…There is considerable evidence for the inhibition of NFkB signaling by calcitriol in PCa cells. Calcitriol decreases the levels of the angiogenic and pro-inflammatory cytokine IL-8 in immortalized normal human prostate epithelial cell lines (HPr-1 and RWPE-1) and established PCa cell lines (LNCaP, PC-3, and DU145; Bao et al 2006a). The suppression of IL-8 by calcitriol appears to be due to the inhibition of NFkB signaling.…”

Antineoplastic effects of 1,25(OH)2D3 and its analogs in breast, prostate and colorectal cancer

“…Supplementing these mice with vitamin D and calcium prevents or mitigates this effect (Bastie et al 2012). As mentioned before, 1,25(OH) 2 D 3 inhibits NF-kB signalization by acting on different members of this pathway (Bao et al 2006a). 1,25(OH) 2 D 3 strongly represses the P65 (RELA) subunit transactivation in BC, PC and CRC cells while it also induces the expression of the NF-kB pathway inhibitor, IkBa (Sun et al 2008, Tse et al 2010.…”

“…Indeed, another study on BC cells shows an increase in intracellular calcium concentrations after 1,25(OH) 2 D 3 stimulation, being a rapid, nongenomic effect that does not involve the VDR. In cancer cells, in contrast to normal mammary cells, this calcium increase induces calpain-mediated apoptosis (Sergeev 2004 (Bao et al 2006a). Moreover, 1,25(OH) 2 D 3 also inhibits an upstream regulator of IL8, namely nuclear factor kappa B (NF-kB), which is thought to be partly responsible for the 1,25(OH) 2 D 3 -mediated IL8 inhibition.…”