State Key Laboratory of Biotherapy, Section of Oncogene, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
J Cell Mol Med. 2018 Jan;22(1):589-599. doi: 10.1111/jcmm.13346. Epub 2017 Oct 11.
The natural agent rhein is an ananthraquinone derivative of rhubarb, which has anticancer effects. To determine the mechanisms underlying the anticancer effects of rhein, we detected the effect of rhein on several oncoproteins. Here, we show that rhein induces β-catenin degradation in both hepatoma cell HepG2 and cervical cancer cell Hela. Treatment of HepG2 and Hela cells with rhein shortens the half-life of β-catenin. The proteasome inhibitor MG132 blunts the downregulation of β-catenin by rhein. The induction of β-catenin degradation by rhein is dependent on GSK3 but independent of Akt. Treatment of HepG2 and Hela cells with GSK3 inhibitor or GSK3β knockdown abrogates the effect of rhein on β-catenin. GSK3β knockdown compromises the inhibition of HepG2 and Hela cell growth by rhein. Furthermore, rhein dose not downregulate β-catenin mutant that is deficient of phosphorylation at multiple residues including Ser33, Ser37, Thr41 and Ser45. Moreover, rhein induces cell cycle arrest at S phase in both HepG2 and Hela cells. Intraperitoneal administration of rhein suppresses tumour cells proliferation and tumour growth in HepG2 xenografts model. Finally, the levels of β-catenin are reduced in rhein-treated tumours. These data demonstrate that rhein can induce β-catenin degradation and inhibit tumour growth.
天然产物大黄酸是大黄的蒽醌衍生物，具有抗癌作用。为了确定大黄酸抗癌作用的机制，我们检测了大黄酸对几种癌蛋白的影响。在这里，我们表明大黄酸在肝癌细胞 HepG2 和宫颈癌细胞 Hela 中诱导β-连环蛋白降解。用大黄酸处理 HepG2 和 Hela 细胞可缩短β-连环蛋白的半衰期。蛋白酶体抑制剂 MG132 可阻止大黄酸下调β-连环蛋白。大黄酸诱导β-连环蛋白降解依赖于 GSK3，但不依赖于 Akt。用 GSK3 抑制剂或 GSK3β 敲低处理 HepG2 和 Hela 细胞可消除大黄酸对β-连环蛋白的作用。GSK3β 敲低可削弱大黄酸对 HepG2 和 Hela 细胞生长的抑制作用。此外，大黄酸不能下调β-连环蛋白突变体，该突变体在多个残基（包括 Ser33、Ser37、Thr41 和 Ser45）处缺乏磷酸化。此外，大黄酸可诱导 HepG2 和 Hela 细胞的细胞周期停滞在 S 期。腹腔内给予大黄酸可抑制 HepG2 异种移植模型中的肿瘤细胞增殖和肿瘤生长。最后，在大黄酸处理的肿瘤中β-连环蛋白的水平降低。这些数据表明，大黄酸可以诱导β-连环蛋白降解并抑制肿瘤生长。
