Reduced 1alpha-hydroxylase activity in human prostate cancer cells correlates with decreased susceptibility to 25-hydroxyvitamin D3-induced growth inhibition.
Reduced 1alpha-hydroxylase activity in human prostate cancer cells correlates with decreased susceptibility to 25-hydroxyvitamin D3-induced growth inhibition.
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发表时间：
2001-04
期刊：
影响因子：
11.2
通讯作者：
J. Hsu;D. Feldman;J. McNeal;D. Peehl
中科院分区：
文献类型：
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作者：
J. Hsu;D. Feldman;J. McNeal;D. Peehl
来自流行病学、分子和遗传学研究的证据表明，维生素D在前列腺癌的发生和/或进展中起着作用。在实验模型和临床试验中，1，25-二羟基维生素D3[1，25(OH)2D3]被证明对前列腺上皮细胞具有抗增殖、分化和抗肿瘤/侵袭作用。由于高钙血症的主要副作用限制了1，25(OH)2D3的直接临床应用，我们研究了其钙化较少的前体25-羟基维生素D3[25(OH)D3]的潜在治疗作用，该前体通过1α-羟基酶在前列腺内局部转化为1，25(OH)2D3。用酶-底物反应法定量测定人前列腺上皮细胞的1α-羟基酶活性，发现腺癌来源的细胞比正常组织或良性前列腺增生症(BPH)来源的细胞活性显著降低。在生长分析中，我们发现25(OH)D3对正常或BPH细胞的生长抑制作用类似于1，25(OH)2D3。相反，在癌细胞和已建立的细胞系的原代培养中，25(OH)D3的抗增殖作用明显低于1，25(OH)2D3。我们的结果表明，25(OH)D3对生长的抑制依赖于内源性1α-羟基酶的活性，而这种活性在前列腺癌细胞中是缺乏的。这一发现对维生素D化合物预防和治疗前列腺癌具有重要意义。
Evidence from epidemiological, molecular, and genetic studies suggests a role for vitamin D in the development and/or progression of prostate cancer. In experimental models and clinical trials, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] was shown to exert antiproliferative, prodifferentiating, and antimetastatic/invasive effects on prostatic epithelial cells. Because the direct clinical application of 1,25(OH)2D3 is limited by the major side effect of hypercalcemia, we investigated the potential therapeutic utility of its less calcemic precursor, 25-hydroxyvitamin D3 [25(OH)D3], which is converted locally within the prostate to 1,25(OH)2D3 by 1alpha-hydroxylase. Quantification of 1alpha-hydroxylase activity in human prostatic epithelial cells by enzyme-substrate reaction analyses revealed a significantly decreased activity in cells derived from adenocarcinomas compared with cells derived from normal tissues or benign prostatic hyperplasia (BPH). In growth assays, we found that 25(OH)D3 inhibited growth of normal or BPH cells similarly to 1,25(OH)2D3. In contrast, in primary cultures of cancer cells and established cell lines, the antiproliferative action of 25(OH)D3 was significantly less pronounced than that of 1,25(OH)2D3. Our results indicate that growth inhibition by 25(OH)D3 depends on endogenous 1alpha-hydroxylase activity, and that this activity is deficient in prostate cancer cells. This finding has ramifications for both the prevention and therapy of prostate cancer with vitamin D compounds.