Association among plasma 1,25(OH)₂D, ratio of 1,25(OH)₂D to 25(OH)D, and prostate cancer aggressiveness

Abstract

Background African‐American (AA) men tend to present with more aggressive prostate cancer (Gleason score >7) than European‐American (EA) men. Vitamin D and its metabolites are implicated in prostate cancer biology with vitamin D deficiency, indicated by its metabolite levels in serum or plasma, usually observed in AA men. Objective To determine if 1, 25‐dihydroxy vitamin D3 [1,25(OH) 2 D] plasma levels in AA and EA prostate cancer patients alter the risk of having aggressive prostate cancer. Design Research subjects from the North Carolina‐Louisiana Prostate Cancer Project (AA n = 435 and EA n = 532) were included. Plasma metabolites 1,25(OH) 2 D and 25‐hydroxyvitamin D3 [25(OH)D] were measured using liquid chromatography with tandem mass spectrophotometry. Research subjects were classified into low (Gleason sum < 7, stage T1‐T2, and Prostate‐specific antigen (PSA) < 9 ng/mL) or high (Gleason sum > 8 or Gleason sum = 7 with 4 + 3, or PSA > 20 ng/mL, or Gleason sum = 7 and stage T3‐T4) aggressive disease. Results Research subjects in the second and third tertiles of plasma levels of 1, 25(OH) 2 D had lower odds of high aggressive prostate cancer (AA [OR T2vsT1 : 0.66, 95%CI: 0.39‐1.12; OR T3vsT1 : 0.83, 95%CI: 0.49‐1.41] and EA [OR T2vsT1 : 0.68, 95%CI: 0.41‐1.11; OR T3vsT1 : 0.67, 95%CI: 0.40‐1.11]) compared with the first tertile, though confidence intervals included the null. Greater 1,25(OH) 2 D/25(OH)D molar ratios were associated with lower odds of high aggressive prostate cancer more evidently in AA (OR Q4vsQ1 : 0.45, CI: 0.24‐0.82) than in EA (OR Q4vsQ1 : 0.64, CI: 0.35‐1.17) research subjects. Conclusions The 1,25(OH) 2 D/25(OH)D molar ratio was associated with decreased risk of high aggressive prostate cancer in AA men, and possibly in EA men. Further studies analyzing vitamin D polymorphisms, vitamin D binding protein levels, and prostatic levels of these metabolites may be useful. These studies may provide a better understanding of the vitamin D pathway and its biological role underlying health disparities in prostate cancer.

Vitamin D Sufficiency Enhances Differentiation of Patient-Derived Prostate Epithelial Organoids

“…The relationship between vitamin D dysregulation and aggressive disease is supported by rodent models, where prostatic VDR deletion within the TgAPT mouse model of prostate carcinogenesis increased adenocarcinoma foci number and area (Fleet et al, 2019). The relationship is also observed in patients, where vitamin D deficiency is associated with risk of aggressive PCa (Fang et al, 2011;Giovannucci et al, 2006;Murphy et al, 2014;Ramakrishnan et al, 2019;Studzinski and Moore, 1995). Vitamin D deficiency is especially pertinent to PCa patients who are frequently deficient due to high skin melanin content, such as African Americans, (Murphy et al, 2014) or lack of sun exposure (Gilbert et al, 2009), such as the elderly (Elshazly et al, 2017).…”

Vitamin D-Induced Molecular Mechanisms to Potentiate Cancer Therapy and to Reverse Drug-Resistance in Cancer Cells

“…The relationship between vitamin D and prostate cancer risk is still controversial, due to contradictory data reporting an inverse correlation [62,73,76,79,96], or a direct correlation [78,97], or even the absence of any correlation [74,75,77] between 25(OH)D levels and prostate cancer. Interestingly, a recent meta-analysis of 21 observational studies suggests a negative role of vitamin D in prostate cancer, by reporting a direct correlation between high 25(OH)D levels and prostate cancer risk (OR: 1.17, 95% CI: 1.05 to 1.30, p = 0.004), therefore inviting to caution in vitamin D supplementation [97].…”

“…Several observational studies have shown that circulating levels of 25(OH)D, used as surrogate marker for the evaluation of vitamin D status, may be associated with cancer risk [ 5 , 6 , 56 , 57 , 58 , 59 ] and prognosis [ 6 , 60 , 61 , 62 , 63 , 64 , 65 ]. A strong association between low 25(OH)D circulating levels and colorectal [ 6 , 56 , 60 , 61 , 66 , 67 , 68 , 69 , 70 , 71 , 72 ], prostate [ 59 , 62 , 63 , 73 , 74 , 75 , 76 , 77 , 78 , 79 ] and breast [ 52 , 58 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 ] cancer risk has been reported.…”

Vitamin D, gut microbiota, and radiation-related resistance: a love-hate triangle

“…Furthermore, Findlay et al showed that 1α,25(OH)2D3 enhanced radiation sensitivity in colorectal cancer cells through regulating the EMT [42]. Higher plasma levels of 25(OH)D3 are associated with a decreased risk of highly aggressive prostate cancer [43]. Mutation or deficiency of the genes and enzymes responsible for the transport or metabolism of 25(OH)D3 may alter its levels and functions [43].…”

“…Higher plasma levels of 25(OH)D3 are associated with a decreased risk of highly aggressive prostate cancer [43]. Mutation or deficiency of the genes and enzymes responsible for the transport or metabolism of 25(OH)D3 may alter its levels and functions [43]. For instance, a mutation in CYP2R1, a key hydroxylase for 25(OH)D3 production, resulted in deficiency thereof, as well as symptoms of vitamin D-dependent rickets [44].…”