Dihydrotestosterone induces p27 degradation via direct binding with SKP2 in ovarian and breast cancer.
Dihydrotestosterone induces p27 degradation via direct binding with SKP2 in ovarian and breast cancer.
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DOI：
10.3892/ijmm.2011.677
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发表时间：
2011-07
影响因子：
5.4
通讯作者：
Pengcheng Shi;Y. Zhang;X. Tong;Yu Yang;Z. Shao
中科院分区：
文献类型：
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作者：
Pengcheng Shi;Y. Zhang;X. Tong;Yu Yang;Z. Shao
雄激素在卵巢癌和乳腺癌中预防或促进细胞周期进展的作用是有争议的。这种效应决定了绝经后患者术后如何正确治疗的基本规律。在本研究中，我们研究了不同的雄激素，即双氢睾酮（DHT），睾酮和脱氢表雄酮（DHEA）在MCF-7乳腺癌和OVCAR-3卵巢癌细胞中的作用。我们发现DHT可以在4 h内下调p27，而不下调p21。进一步的研究证明DHT通过泛素-蛋白酶体蛋白水解途径诱导p27降解。抑制雄激素受体和磷酸化不妨碍降解。然而，蛋白水解抑制剂可有效拮抗dht诱导的p27降解。敲低s期激酶相关蛋白2 （SKP2）而非Kip1泛素化促进复合物1 （KPC1）也能阻止p27的下调。DHT导致p27与SKP2直接结合，而不受磷酸化状态的影响。总的来说，DHT调节MCF-7和OVCAR-3细胞中p27的降解，而不是其他被检测的雄激素。此外，SKP2被证明可以作为DHT受体。
The effect of androgens on the prevention or promotion of cell cycle progression in ovarian and breast cancer is controversial. This effect determines the basic rules of how to treat postmenopausal patients properly after surgery. In the present study, we investigated the effects of different androgens, namely dihydrotestosterone (DHT), testosterone and dehydroepiandrosterone (DHEA) in MCF-7 breast cancer and OVCAR-3 ovarian cancer cells. We found that DHT could down-regulate p27, but not p21, within 4 h. Further studies proved that DHT induced p27 degradation through the ubiquitin-proteasome proteolytic pathway. Inhibition of the androgen receptor and of phosphorylation did not hamper the degradation. However, proteolysis inhibitors effectively antagonized the DHT-induced p27 degradation. Knockdown of the S-phase kinase-associated protein 2 (SKP2), rather than of the Kip1 ubiquitination promoting complex 1 (KPC1), also prevented p27 down-regulation. DHT led to the direct binding of p27 to SKP2 independent of the phosphorylation status. Collectively, DHT, but not the other examined androgens regulated the degradation of p27 in MCF-7 and OVCAR-3 cells. Furthermore, SKP2 was shown to act as a DHT receptor.