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25-Hydroxy-Vitamin D Metabolism in Human Colon Cancer Cells during Tumor Progression

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Abstract

RT-PCR analysis showed elevated expression of 25-hydroxyvitamin D-1α-hydroxylase (1α-OHase) and of 25-hydroxyvitamin D-24-hydroxylase (24-OHase) in well differentiated human colon carcinomas in comparison to normal mucosa. Further tumor progression is associated with a rise in 1α-OHase but with no significant change in 24-OHase mRNA expression. Accordingly, HPLC analysis of 25-hydroxy-vitamin D3 metabolism in freshly isolated tumor cells indicated that well to moderately differentiated colon cancers in situ are able to produce 1α,25-dihydroxyvitamin D3 (1α,25-(OH)2D3) and convert it through 24-OHase activity into side-chain modified metabolites, 1,24,25-(OH)3-D3 and 1,25-(OH)2- 24-oxo-D3. Likewise, 25-(OH)-D3 is metabolized into 24,25-(OH)2D3, 23,25-(OH)2D3, and 23,25-(OH)2-24-oxo-D3. Poorly-differentiated cancers expressed low levels of 1α-OHase mRNA, whereas 24-OHase was even over-expressed. RT-PCR and HPLC analysis of vitamin D metabolism in primary culture cell clones strongly suggested that the extent of endogenously produced 1α,25-(OH)2-D3 was inversely related to 24-OHase activity, which could thus limit the antimitotic efficacy of 1α,25-(OH)2-D3 particularly at late stages of colon cancer progression.

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To whom correspondence should be addressed at Department of Pathophysiology, University of Vienna Medical School, Waehringer Guertel 18–20, A-1090 Vienna, Austria. Fax: 43-1-40400-5120. E-mail: [email protected].

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