Vitamin D and Hypoxia: Points of Interplay in Cancer

SIMPLE SUMMARY: Vitamin D, conventionally considered a nutrient, is a potent hormone regulating many physiological functions. In addition, many studies point to the anticancer activities of calcitriol. However, cancer cells use mechanisms that negate the beneficial effects of calcitriol. Many of these mechanisms control or are controlled by the Hypoxia Inducible transcription Factors (HIFs) that are overexpressed in human cancers due to the development of hypoxia inside the tumors. This review discusses the crosstalk between calcitriol and HIF signaling in order to better understand their relationship to cancer, its prevention, and treatment. ABSTRACT: Vitamin D is a hormone that, through its action, elicits a broad spectrum of physiological responses ranging from classic to nonclassical actions such as bone morphogenesis and immune function. In parallel, many studies describe the antiproliferative, proapoptotic, antiangiogenic effects of calcitriol (the active hormonal form) that contribute to its anticancer activity. Additionally, epidemiological data signify the inverse correlation between vitamin D levels and cancer risk. On the contrary, tumors possess several adaptive mechanisms that enable them to evade the anticancer effects of calcitriol. Such maladaptive processes are often a characteristic of the cancer microenvironment, which in solid tumors is frequently hypoxic and elicits the overexpression of Hypoxia-Inducible Factors (HIFs). HIF-mediated signaling not only contributes to cancer cell survival and proliferation but also confers resistance to anticancer agents. Taking into consideration that calcitriol intertwines with signaling events elicited by the hypoxic status cells, this review examines their interplay in cellular signaling to give the opportunity to better understand their relationship in cancer development and their prospect for the treatment of cancer.