Prevention of Renal Cell Carcinoma by Active Vitamin D3

Abstract

We studied the serum levels of 1,25-dihydroxyvitamin D [1,25(OH)₂D (Vit D)] in patients with renal cell carcinoma (RCC) and the influence of 1,25(OH)₂D₃ (Vit D₃) on gap junctional intercellular communication (GJIC) during carcinogenesis. The serum Vit D levels were measured by a competitive protein-binding assay using the chromatographic method. Using the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) assay, noncytotoxic concentrations of Vit D₃ and the tumor promoters N-nitrosodimethylamine (NDMA) and N-ethyl-N-hydroxyethylnitrosamine (EHEN) were tested against cultured human renal proximal tubular cells (HRPTCs). GJIC function was assayed by the scrape-loading dye transfer technique. Cx43 mRNA expression was also examined by the reverse transcriptase-polymerase chain reaction (RT-PCR). Serum Vit D levels in patients with RCC were lower than those in controls (p < 0.001). Patients with T3 to T4 (rapid-growth) tumors had lower levels of Vit D than did patients with T1 to T2 (slow-growth) tumors (p < 0.001). Vit D₃ enhanced the GJIC function of HRPTCs (p < 0.05), whereas NDMA and EHEN suppressed it (p < 0.05). When the cells were treated with tumor promoters and Vit D₃ simultaneously, the GJIC functions remained at pretreatment levels. We also demonstrated Cx43 mRNA expression in RPTECs treated with EHEN and VitD₃ simultaneously. These data suggest that a decrease in the serum Vit D level is one of the risk factors for development and progression of RCC, and Vit D₃ may prevent RCC by preserving GJIC during carcinogenesis.