Involvement of the retinoblastoma (pRb)-E2F/DP pathway during anti proliferative effects of resveratrol in human epidermoid carcinoma (A431) cells
Involvement of the retinoblastoma (pRb)-E2F/DP pathway during anti proliferative effects of resveratrol in human epidermoid carcinoma (A431) cells
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DOI：
10.1006/bbrc.2001.5819
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发表时间：
2001-11-02
影响因子：
3.1
通讯作者：
Ahmad, N
中科院分区：
文献类型：
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作者：
Adhami, VM;Afaq, F;Ahmad, N
白藜芦醇（反式-3，4 '，5-三羟基芪）是一种多酚类植物抗毒素，存在于葡萄、坚果、许多其他水果和红酒中，是一种有效的抗氧化剂，具有抗氧化和预防癌症的特性。白藜芦醇赋予癌症化学预防作用的机制尚未明确定义。早些时候，我们已经表明，白藜芦醇处理导致诱导细胞周期蛋白激酶抑制剂WAF 1/CIP 1/p21，通过抑制细胞周期蛋白（E，D1和D2）和细胞周期蛋白依赖性激酶。(cdk2，cdk 4和cdk 6），导致A431人表皮样癌细胞的G（0）/G（1）期停滞，随后凋亡（Ahmad等人，7，1466-1473，2001）。视网膜母细胞瘤(pRb)E2 F家族转录因子是重要的蛋白质，它们在细胞周期的G（1）-->S期转变及其附近调节细胞周期的进程。在这里，我们提供的证据参与的pRb-E2 F/DP通路作为白藜芦醇介导的细胞周期阻滞和凋亡的重要贡献者。免疫印迹分析表明白藜芦醇。A431细胞的处理导致pRb的过度磷酸化形式的剂量依赖性和时间依赖性降低，而低磷酸化pRb相对增加。这种反应伴随着所有五个E2 F（1-5）家族成员的转录因子及其异二聚体伙伴DP 1和DP 2的蛋白质表达下调。这表明，白藜芦醇导致过度磷酸化的pRb蛋白的下调与相对增加的低磷酸化的pRb，这反过来又与游离E2 F的可用性妥协。我们认为，这一系列的事件导致细胞周期进程在G（1）->S期转变的停止，从而导致G（0）/G（1）停滞和随后的凋亡性细胞死亡。据我们所知，这是第一个研究表明参与pRb-E2 F/DP途径作为白藜芦醇的癌症化学预防作用的机制。(C)北京：科学出版社.
Resveratrol (trans-3,4 ' ,5-trihydroxystilbene), a polyphenolic phytoalexin found in grapes, nuts, many other fruits, and red wine, is a potent antioxidant with antiinflammatory and cancer-preventive properties. The mechanism(s) by which resveratrol imparts cancer chemopreventive effects has not been clearly defined. Earlier, we have shown that resveratrol treatment results in an induction of the cyclin kinase inhibitor WAF1/CIP1/p21 which, by inhibiting cyclin (E, D1, and D2) and cyclin-dependent kinases. (cdk2, cdk4, and cdk6), results in a G(0)/G(1)-phase arrest followed by apoptosis of A431 human epidermoid carcinoma cells (Ahmad et al., Clin. Cancer Res. 7, 1466-1473, 2001). Retinoblastoma. (pRb) and the E2F family of transcription factors are important proteins, which regulate the progression of the cell cycle at and near the G(1)-->S phase transition. Here we provide evidence for the involvement of the pRb-E2F/DP pathway as an important contributor of resveratrol-mediated cell cycle arrest and apoptosis. Immunoblot analysis demonstrated that resveratrol. treatment of A431 cells results in a dose- as well as time-dependent decrease in the hyperphosphorylated form of pRb with a relative increase in hypophosphorylated pRb. This response was accompanied by downregulation of protein expression of all five E2F (1-5) family members of transcription factors studied and their heterodimeric partners DP1 and DP2. This suggests that resveratrol causes a downregulation of hyperphosphorylated pRb protein with a relative increase in hypophosphorylated pRb that, in turn, compromises with the availability of free E2F. We suggest that this series of events results in a stoppage of the cell cycle progression at the G(1)-->S phase transition thereby leading to a G(0)/G(1) arrest and subsequent apoptotic cell death. To our knowledge, this is the first study showing the involvement of the pRb-E2F/DP pathway as a mechanism of the cancer-chemopreventive effects of resveratrol. (C) 2001 Academic Press.