Vitamin D in Inflammation and Cancer

Vitamin D is obtained in an inactive form from sun exposure, food or supplements and in order to become activated, it must be hydroxylated through 2 enzymatic reactions in liver and kidney. The first step of vitamin D metabolism starts in small intestine where it is absorbed with other dietary fats [51]. Once these fats entered into lumen, bile acids release, which emulsify and form lipid-containing micelles facilitating its diffusion into enterocytes [52]. Once absorbed, vitamin D is packaged into chylomicrons and has to face 2 fates: a part is transported into liver, and the other fraction is taken up by skeletal muscles and adipose tissue [53]. In the liver, Vitamin D binding protein (DBP)- a specific carrier protein- facilitates their transport into hepatocytes and other tissues.

Ultraviolet B radiation (UBV) converts pro-vitamin D3 (7-Dehydrocholesterol) to the pre-vitamin D3 form (pre-calciferol). In the epidermis, it can be subjected to thermal isomerization into vitamin D (Fig. 1). Alternatively, another non-active forms like tachysterol and lumisterol can be produced through photoisomerization of pro-vitamin D3. These non-active forms may exert different biological functions [54]. A number of factors including UBV radiation quality and intensity, availability of 7-dehydrocholesterol and characteristics of the skin control the production of vitamin D3 in the skin.

The three main enzymes responsible for vitamin D metabolism are: CYP27A, CYP27B1 and CYP24B1. In the liver, CYP27A1 hydroxylates vitamin D into 25(OH)D. full activation occurs in the kidney where CYP27B1 catalyzes 25(OH)D into the active form 1,25(OH)2D3 which is responsible for the biological effects in humans. 1,25(OH)2D3 is inversely converted into its inactive form via CYP24A1 which represents the limiting step of vitamin D activation as 1,25(OH)2D3 highly induces its expression. This enzyme also found to be highly expressed in cancer tissues and promotes cancer progression as a result of vitamin D insufficiency [55].

Sun H et al. proposed CYP24A1 as a potential diagnostic biomarker for progression of colorectal cancer in a study of 99 patients with colorectal cancer [56]. They found that elevated protein levels of CYP24A1 induced deeper tumour invasion, lymph node metastases and venous permeation. With these observations, CYP24A1 is considered as a pro-oncogenic protein. One plausible mechanism for this effects is that increase the expression levels of CYP24A1 results in deactivation of 1,25(OH)2D3, hence halting its antitumor effects in CRC [56, 57]. Recently, Shiratsuchi et al. found that increased expression of CYP24A1 counteracts the anti-proliferative and growth inhibitory properties of 1,25(OH)2D3 in a model of lung cancer xenograft in vivo and that this catabolic enzyme could be considered as a potential oncogene in lung cancer [58]. Not just in colorectal cancer and lung cancer, CYP24A1 also have been shown to have a pro-survival stimulatory oncogenic effects in breast carcinoma cells as shown by Osani M et al. [59] when they suppress the constitutive expression of CYP24A1 and found that tumor growth has been reduced significantly in vivo [59].

Wei Luo et al. screened small molecules library to identify possible inhibitors of CYP24A1 and discovered a new protein kinase CK2 inhibitor named 4,5,6,7-tetrabromobenzimidazole (TBBz) that significantly augments 1,25(OH)2D3-mediated antitumor effects both in vitro and in vivo in prostate cancer cells and xenografts [60]. These results suggest that the inhibition of CYP24A1 both on mRNA and protein levels and finding novel inhibitors of CYP24A1 could serve as a successful strategy for increasing the anti-cancerous effects of 1,25(OH)2D3.