Retinoic acid decreases ATF-2 phosphorylation and sensitizes melanoma cells to taxol-mediated growth inhibition.
Retinoic acid decreases ATF-2 phosphorylation and sensitizes melanoma cells to taxol-mediated growth inhibition.
复制标题
视黄酸会降低ATF-2磷酸化，并使黑色素瘤细胞对紫杉醇介导的生长抑制敏感。
DOI：
10.1186/1750-2187-3-3
复制
发表时间：
2008-02-12
影响因子：
--
通讯作者：
Niles, Richard M
中科院分区：
文献类型：
--
作者：
Huang, Ying;Minigh, Jennifer;Miles, Sarah;Niles, Richard M
皮肤黑色素瘤通常对化疗和放疗有抵抗力。这种耐药性最近被证明是由于，至少部分是由于高激活转录因子2（ATF-2）在这些肿瘤中的活性。与这些报道一致，我们发现B16小鼠黑色素瘤细胞比永生化但非恶性的小鼠黑色素细胞具有更高水平的ATF-2。此外，黑色素瘤细胞具有比永生化黑色素细胞高得多的磷酸化（活性）ATF-2的量。在确定维甲酸（RA）如何刺激B16黑色素瘤中活化蛋白-1（AP-1）活性的过程中，我们发现这种维甲酸降低ATF-2的磷酸化。这种作用似乎是通过p38 MAPK介导的，因为RA降低了p38磷酸化，并且p38 MAPK的选择性抑制剂（SB 203580）也抑制了ATF-2的磷酸化。由于ATF-2活性似乎参与了黑色素瘤对化疗的抗性，我们测试了用RA治疗黑色素瘤细胞会使它们对紫杉醇的生长抑制作用敏感的假设。我们发现用RA预处理B16细胞使紫杉醇的IC 50从50 nM降低到1 nM。在这些研究结果和我们以前的工作AP-1的基础上，我们提出了一个模型，其中RA治疗B16细胞减少ATF-2的磷酸化，这导致较少的二聚体形成与六月。“自由”的六月，然后可以形成异源二聚体与Fos，导致增加AP-1的活性在RA处理的B16细胞中观察到。从主要的ATF-2：Jun二聚体到更高量的Jun：Fos二聚体的平衡转移可能导致靶基因表达的变化，从而降低对化疗药物的抗性，并有助于RA抑制增殖和诱导分化的途径。
Cutaneous melanoma is often resistant to chemo- and radiotherapy. This resistance has recently been demonstrated to be due, at least in part, to high activating transcription factor 2 (ATF-2) activity in these tumors. In concordance with these reports, we found that B16 mouse melanoma cells had higher levels of ATF-2 than immortalized, but non-malignant mouse melanocytes. In addition, the melanoma cells had a much higher amount of phosphorylated (active) ATF-2 than the immortalized melanocytes. In the course of determining how retinoic acid (RA) stimulates activating protein-1 (AP-1) activity in B16 melanoma, we discovered that this retinoid decreased the phosphorylation of ATF-2. It appears that this effect is mediated through p38 MAPK, because RA decreased p38 phosphorylation, and a selective inhibitor of p38 MAPK (SB203580) also inhibited the phosphorylation of ATF-2. Since ATF-2 activity appears to be involved in resistance of melanoma to chemotherapy, we tested the hypothesis that treatment of the melanoma cells with RA would sensitize them to the growth-inhibitory effect of taxol. We found that pretreatment of B16 cells with RA decreased the IC50 from 50 nM to 1 nM taxol. On the basis of these findings and our previous work on AP-1, we propose a model in which treatment of B16 cells with RA decreases the phosphorylation of ATF-2, which results in less dimer formation with Jun. The "freed-up" Jun can then form a heterodimer with Fos, resulting in the increased AP-1 activity observed in RA-treated B16 cells. Shifting the balance from predominantly ATF-2:Jun dimers to a higher amount of Jun:Fos dimers could lead a change in target gene expression that reduces resistance to chemotherapeutic drugs and contributes to the pathway by which RA arrests proliferation and induces differentiation.