Inhibition of MCF-7 breast cancer cell proliferation by 5α-dihydrotestosterone;: a role for p21Cip/Waf1
Inhibition of MCF-7 breast cancer cell proliferation by 5α-dihydrotestosterone;: a role for p21Cip/Waf1
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DOI：
10.1677/jme.0.0320793
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发表时间：
2004-06-01
影响因子：
3.5
通讯作者：
Bentel, JM
中科院分区：
文献类型：
--
作者：
Greeve, MA;Allan, FK;Bentel, JM
雄激素在体外和体内抑制乳腺癌细胞生长的机制尚不清楚。在这项研究中，用雄激素 5α-二氢睾酮 (DHT) 处理异步生长的 MCF-7 乳腺癌细胞，结果显示可抑制细胞增殖并诱导 G1 期细胞比例适度增加。与针对 G1-S 相转变的目标一致，MCF-7 培养物的 DHT 预处理阻止了血清诱导的 G1 停滞细胞进入 S 期，并在 3 天内将细胞周期蛋白依赖性激酶 (Cdk)4 和 Cdk2 的激酶活性降低至对照的 50% 以下。 DHT 治疗与 Cdk 抑制剂 P27(Kip1) 水平增加两倍以上相关，而 p21(Cip1/Waf1) 蛋白水平保持不变。在 DHT 治疗的前 24 小时内，Cck4 相关 p21(Cip1/Waf1) 和 P27(Kip1) 水平降低，同时 Cdk4 相关细胞周期蛋白 D3 水平降低。相比之下，DHT处理导致Cdk2相关的p21(cip1)/(Waf1)积累增加，而与Cdk2复合物结合的p27(Kip1)水平没有显着改变。这些发现表明，DHT 逆转了 Cdk4 介导的 p21(Cip1/Waf1) 和 p27(Kip1) 滴定，使其远离 Cdk2 复合物，并且 p21(Cip1/Waf1) 与 Cdk2 复合物的关联增加部分介导了雄激素诱导的乳腺癌细胞生长抑制。
Androgens inhibit the growth of breast cancer cells in vitro and in vivo by mechanisms that remain poorly defined. In this study, treatment of asynchronously growing MCF-7 breast cancer cells with the androgen, 5alpha-dihydrotestosterone (DHT), was shown to inhibit cell proliferation and induce moderate increases in the proportion of G1 phase cells. Consistent with targeting the G1-S phase transition, DHT pretreatment of MCF-7 cultures impeded the serum-induced progression of G1-arrested cells into S phase and reduced the kinase activities of cyclin-dependent kinase (Cdk)4 and Cdk2 to less than 50% of controls within 3 days. DHT treatment was associated with greater than twofold increases in the levels of the Cdk inhibitor, P27(Kip1), while p21(Cip1/Waf1) protein levels remained unchanged. During the first 24 h of DHT treatment, levels of Cck4-associated p21(Cip1/Waf1) and P27(Kip1) were reduced coinciding with decreased levels of Cdk4-associated cyclin D3. In contrast, DHT treatment caused increased accumulation of Cdk2-associated p21(cip1)/(Waf1), with no significant alterations in levels of p27(Kip1) bound to Cdk2 complexes. These findings suggest that DHT reverses the Cdk4-mediated titration of p21(Cip1/Waf1) and p27(Kip1) away from Cdk2 complexes, and that the increased association of p21(Cip1/Waf1) with Cdk2 complexes in part mediates the androgen-induced growth inhibition of breast cancer cells.