Depleting ovarian cancer stem cells with calcitriol

Abstract

Cancer stem cells (CSCs) represent the root of many solid tumors including ovarian cancer. Eradication of CSCs represents a novel cancer therapeutic strategy. Calcitriol, also known as 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], is an active metabolite of vitamin D, functioning as a potent steroid hormone. Calcitriol has shown anti-tumor effects in various cancers by regulating multiple signaling pathways. It has been reported that calcitriol can regulate the properties of normal and CSCs. However, the effect of calcitriol on the ovarian cancer growth and ovarian CSCs is still unclear. Here, by using a mouse subcutaneous xenograft model generated with human ovarian cancer cells, we have demonstrated that administration of calcitriol is able to strikingly delay the tumor growth. Calcitriol treatment can also deplete the ovarian CSC population characterized by ALDH⁺ and CD44⁺CD117⁺; decrease their capacity to form sphere under the CSC culture condition, and reduce the frequency of tumor-initiating cells, as evaluated by in vivo limiting dilution analysis. Mechanistic investigation revealed that calcitriol depletes CSCs via the nuclear vitamin D receptor (VDR)-mediated inhibition of the Wnt pathway. Furthermore, the activation of VDR pathway is more sensitive to calcitriol in ovarian CSCs than in non-CSCs, although the expression levels of VDR are comparable. Taken together, our data indicate that calcitriol is able to deplete the ovarian CSC population by inhibiting their Wnt signaling pathway, consequently, impeding the growth of xenograft tumors.