Calcitriol enhancement of TPA-induced tumorigenic transformation is mediated through vitamin D receptor-dependent and -independent pathways
Calcitriol enhancement of TPA-induced tumorigenic transformation is mediated through vitamin D receptor-dependent and -independent pathways
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DOI：
10.1023/a:1018439329996
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发表时间：
1997-11-01
影响因子：
4
通讯作者：
Prince, CW
中科院分区：
文献类型：
--
作者：
Chang, PL;Lee, TF;Prince, CW
我们之前的研究表明，1 α，25-二羟基维生素D-3，骨化三醇，增强的酚酯12- o -十四烷酰基酚-13-乙酸酯（TPA）诱导小鼠表皮JB6 C141.5a细胞的致瘤性转化，为了确定骨化三醇是否通过核维生素D受体（VER）依赖性或非依赖性途径调节这种增强，我们使用了维生素D类似物，通过这些机制中的任何一种诱导生物反应。1 α，24-二羟基-22-烯-24-环丙基维生素D-3 (BT)，与骨化三醇一样，与VDR结合并调节转录，抑制细胞生长，刺激非磷酸化骨桥蛋白（OPN）的表达，增强tpa诱导的锚定独立生长（AIG，一项与这些细胞的致瘤性高度相关的体外实验）。25-羟基-16-烯-23-yne-维生素D-3 （AT）刺激钙内流，但对VDR亲和力低，对细胞生长和OPN表达的影响中等。然而，它增强了tpa诱导的致瘤性转化，尽管程度低于BT，因此表明与vdr无关的机制有关。因为1α-羟化酶活动中检测出JB6细胞,可以转换成1α,25-dihydroxy-16-ene-23-yne-vitamin d 3 (V),一个与高亲和力结合VDR的模拟,而且随后可能提高TPA-induced AIG,验证VDR-independent通路是否参与骨化三醇增强肿瘤发生的转换,两个额外的VDR-independent类似物,1α,25-dihydroxy-lumisterol(3),(约)和24 r, 25-dihydroxyvitamin d 3(),进行了测试,模拟约,刺激钙转运且不能在1碳位置进一步羟基化的AS增加了tpa诱导的AIG，而抑制钙内流的AS则没有。这些研究表明一个不依赖于vdr的途径，也许是刺激钙流入？骨化三醇在JB6 C141.5a细胞中增强tpa诱导的致瘤性转化，并通过vdr依赖机制直接影响转录。
We previously showed that 1 alpha,25-dihydroxyvitamin D-3, calcitriol, enhanced phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) induced tumorigenic transformation of mouse epidermal JB6 C141.5a cells, To determine if calcitriol regulates this enhancement through a nuclear vitamin D receptor (VER)-dependent or -independent pathway, we used vitamin D analogs which induce biological responses by either of these mechanisms, In JB6 C141.5a cells, 1 alpha,24-dihydroxy-22-ene-24-cyclopropyl-vitamin D-3 (BT), which like calcitriol binds to VDR and regulates transcription, inhibited cell growth, stimulated expression of nonphosphorylated osteopontin (OPN), and enhanced TPA-induced anchorage independent growth (AIG, an in vitro assay which highly correlates with tumorigenicity of these cells). 25-Hydroxy-16-ene-23-yne-vitamin D-3 (AT), which stimulates calcium influx but has lo tr affinity for VDR, had moderate effects on cell growth and expression of OPN. However, it enhanced TPA-induced tumorigenic transformation, though to a lesser extent than BT, thus suggesting that a VDR-independent mechanism is involved. Since 1 alpha-hydroxylase activity was detected in JB6 cells, AT could be converted into 1 alpha,25-dihydroxy-16-ene-23-yne-vitamin D-3 (V), an analog which binds with high affinity to VDR, and could subsequently enhance TPA-induced AIG, To verify whether the VDR-independent pathway is involved in calcitriol enhancement of tumorigenic transformation, two additional VDR-independent analogs, 1 alpha,25-dihydroxy-lumisterol(3), (JN) and 24R,25-dihydroxyvitamin D-3 (AS), were tested, The analog JN, which stimulates calcium transport and cannot be further hydroxylated at 1-carbon position, increased TPA-induced AIG, while AS, which inhibits calcium influx, did not. These studies suggest that a VDR-independent pathway, perhaps stimulation of calcium influx? and a VDR-dependent mechanism, which directly affects transcription, are involved in calcitriol's enhancement of TPA-induced tumorigenic transformation in JB6 C141.5a cells.