Vitamin D and Hypoxia: Points of Interplay in Cancer

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.

The mechanism of vitamin D3 in preventing colorectal cancer through network pharmacology

“…A study showed that vitamin D3 can inhibit cell proliferation, invasion, and metastasis and promote apoptosis through the PI3K-Akt pathway ( Songyang et al, 2021 ). Vitamin D3 can also interfere with the metabolism of cancer cells, inhibit the growth and proliferation of cancer cells, and play an anti-cancer role through the HIF signaling pathway ( Gkotinakou et al, 2022 ).…”

“…Under the combined effect of these factors, the proliferation, angiogenesis, immune escape, epithelial-mesenchymal transition and the ability of extracellular matrix remodeling of cancer cells are enhanced ( Mylonis et al, 2021 ; Semenza, 2021 ). The existing evidence suggests that ossifying triol can act on the signaling process of HIF pathway, blocking signal transduction, promoting apoptosis of cancer cells and exerting tumor suppressive effects ( Gkotinakou et al, 2022 ). Mitogen-activated protein kinase (MAPK) is an important member of the serine-threonine kinase family and is the main cell proliferation signaling pathway from the cell surface to the nucleus ( Dong et al, 2002 ).…”

Hypoxia signaling and cholesterol/steroidogenic acute regulatory protein 1 axis: interplay and role in alcohol and non-alcohol-related liver diseases

“…Hypoxia is a characteristic feature of tumor microenvironment, which is known to contribute to cancer cell survival and proliferation. Hypoxia is of particular relevance in the development of solid tumors, which ensues due to the disorganized architecture of tumor vasculature, resulting in poor oxygen delivery particularly to inner core of cancer cells [26]. The development of hypoxia in tumors represents a poor prognostic value for cancer patients [27][28][29].…”

Hypoxia and Cancer: From Bench to Bedside

“…This Special Issue of Cancers (two original articles, five reviews), presented by international experts in tumor hypoxia, focuses on the role of hypoxia, or low oxygen levels, in the development and progression of cancer. This Special Issue includes seven papers that discuss various aspects of hypoxia in cancer, including its effects on tumor growth, metastasis, and resistance to therapy [1][2][3][4][5][6][7]. Davis et al discussed the roles of the hypoxiainducible factor (HIF) signaling pathway and the alpha subunits HIF-1α and HIF-2α in driving tumor progression in the hypoxic tumor microenvironment.…”

“…Gkotinakou et al discussed the interplay in cancer hypoxia focusing on vitamin D. They concluded that tumors have adaptive mechanisms that allow them to resist the anticancer effects of vitamin D, which are often attributed to the hypoxic microenvironment of solid tumors and the overexpression of hypoxia-inducible factors (HIFs). HIF-mediated signaling contributes to cancer cell survival, proliferation, and resistance to anticancer agents [4]. Janczy-Cempa et al focused on cellular adaptation to hypoxic stress, characterized by an increase in oxidoreductase activity, which can be exploited in the design of hypoxia-activated prodrugs (HAPs) and fluorescent turn off-on probes.…”