Lovastatin inhibits proliferation of anaplastic thyroid cancer cells through up-regulation of p27 by interfering with the Rho/ROCK-mediated pathway
Lovastatin inhibits proliferation of anaplastic thyroid cancer cells through up-regulation of p27 by interfering with the Rho/ROCK-mediated pathway
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DOI：
10.1016/j.bcp.2011.08.021
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发表时间：
2011-12-01
影响因子：
5.8
通讯作者：
Lee, Wen-Sen
中科院分区：
文献类型：
--
作者：
Zhong, Wen-Bin;Hsu, Sung-Po;Lee, Wen-Sen
以前，我们证明，洛伐他汀，HMG-CoA还原酶抑制剂，诱导凋亡，分化，并抑制人甲状腺未分化癌细胞（ATC）的侵袭力。在此，我们进一步研究了洛伐他汀对ARO细胞生长的影响。洛伐他汀（0-20 μ M）浓度依赖性地减少培养的ATC细胞数量，并将细胞阻滞在细胞周期的G 0/G1期。Western blot分析显示，洛伐他汀可引起ARO细胞中p27和细胞周期蛋白依赖性激酶（CDK）4蛋白水平升高，细胞周期蛋白A2、D3和磷酸化Rb蛋白水平降低，但对p21、细胞周期蛋白D1和E以及CDK 2蛋白水平无明显影响。洛伐他汀处理的ARO细胞中CDK 2-p27复合物的形成增加，CDK 2活性降低。用p27而不是p21反义寡核苷酸预处理ARO细胞可阻止洛伐他汀诱导的ARO细胞G 0/G1期阻滞。甲羟戊酸可完全抑制洛伐他汀诱导的ARO细胞生长抑制和RhoA和Rac 1易位，而香叶基香叶基焦磷酸可部分抑制上述作用。用Rho相关激酶抑制剂Y27632处理ARO细胞，可消除GDPP介导的对lovastatin诱导的抗增殖、上调和延长p27降解的预防作用。综上所述，这些数据表明，洛伐他汀处理引起Rho香叶基香叶基化的减少，这反过来又增加了p27的表达和稳定性，然后抑制ARO细胞增殖。这些数据表明，洛伐他汀作为治疗ATC的多能疗法值得进一步研究。(C)2011 Elsevier Inc. All rights reserved.
Previously, we demonstrated that lovastatin, a HMG-CoA reductase inhibitor, induced apoptosis, differentiation, and inhibition of invasiveness of human anaplastic thyroid carcinoma cells (ATCs). Here, we further examined the effect of lovastatin on the growth of ARO cells. Lovastatin (0-20 mu M) concentration-dependently decreased cell number in cultured ATC and arrested the cell at the G0/G1 phase of the cell cycle. Western blot analysis revealed that lovastatin caused an increase of the protein level of p27 and cyclin-dependent kinase (CDK)4 and a decrease of the protein level of cyclin A2, cyclin D3, and phosphorylated Rb (pRb), but did not significantly change the protein levels of p21, cyclins D1 and E, and CDK2, in ARO cells. The formation of the CDK2-p27 complex was increased and the CDK2 activity was decreased in the lovastatin-treated ARO cells. Pretreatment of ARO cells with a p27, but not p21, antisense oligonucleotide prevented the lovastatin-induced G0/G1 arrest in ARO cells. The lovastatin-induced growth inhibition and translocation of RhoA and Rac1 in ARO cells were completely prevented by mevalonate and partially by geranylgeranyl pyrophosphate. Treatment of ARO cells with Y27632, an inhibitor of Rho-associated kinase, abolished the GGPP-mediated prevention of lovastatin-induced anti-proliferation and up-regulation and prolonged degradation of p27. Taken together, these data suggest that lovastatin treatment caused a reduction of Rho geranylgeranylation, which in turn increased the expression and stability of p27, and then inhibited ARO cell proliferation. These data suggest that lovastatin merits further investigation as multipotent therapy for treatment ATC. (C) 2011 Elsevier Inc. All rights reserved.