Nayeri S, Danielsson C, Kahlen J P, Schräder M, Mathiasen I S, Binderup L, Carlberg C
Clinique de Dermatologie, Hôpital Cantonal Universitaire, Genève, Switzerland.
Oncogene. 1995 Nov 2;11(9):1853-8.
The hormone 1,25-dihydroxyvitamin D3 (VD) is able to induce cellular differentiation and to inhibit cellular proliferation, which provides it with an interesting therapeutic potential in cancer. However, side effects of VD on homeostasis (eg hypercalcemia) had made the need for the development of VD analogues with low calcemic effect. On the human breast cancer cell line MCF-7 we obtained with the VD analogue EB1089 an about 100-fold higher anti-proliferative effect than with VD. We found that this difference in biological activity is neither related to increased functional affinity to the VD receptor nor to repression of AP-1 activity. The physiologically most prominent complex of the VD receptor is a heterodimer with the retinoid X receptor that binds VD response elements formed two hexameric core binding motifs being arranged either as direct repeats spaced by 3 nucleotides (DR3s) or as inverted palindromes spaced by 9 nucleotides (IP9s). We observed that EB1089 stimulates transcriptional activation from IP9-type elements at clearly lower concentrations than from DR3-type elements. It is possible that IP9-type response elements play an important role in or contribute to the control of cell proliferation, so that promoter-selectivity may explain the high anti-proliferative effect of EB1089.
激素1,25 - 二羟基维生素D3（VD）能够诱导细胞分化并抑制细胞增殖，这使其在癌症治疗方面具有潜在的应用价值。然而，VD对体内稳态的副作用（如高钙血症）使得开发低钙血症效应的VD类似物成为必要。在人乳腺癌细胞系MCF - 7中，我们发现VD类似物EB1089的抗增殖作用比VD高约100倍。我们发现这种生物活性的差异既与对VD受体功能亲和力的增加无关，也与AP - 1活性的抑制无关。VD受体在生理上最主要的复合物是与视黄酸X受体形成的异二聚体，它结合VD反应元件，这些元件由两个六聚体核心结合基序组成，排列方式为间隔3个核苷酸的直接重复序列（DR3s）或间隔9个核苷酸的反向回文序列（IP9s）。我们观察到，EB1089在明显低于DR3型元件的浓度下就能刺激IP9型元件的转录激活。IP9型反应元件可能在细胞增殖的控制中起重要作用或对其有贡献，因此启动子选择性可能解释了EB1089的高抗增殖作用。
