Law Brian K, Chytil Anna, Dumont Nancy, Hamilton Elizabeth G, Waltner-Law Mary E, Aakre Mary E, Covington Cassondra, Moses Harold L
Department of Cancer Biology. Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Mol Cell Biol. 2002 Dec;22(23):8184-98. doi: 10.1128/MCB.22.23.8184-8198.2002.
Transforming growth factor beta (TGF-beta) induces cell cycle arrest of most nontransformed epithelial cell lines. In contrast, many human carcinomas are refractory to the growth-inhibitory effect of TGF-beta. TGF-beta overexpression inhibits tumorigenesis, and abolition of TGF-beta signaling accelerates tumorigenesis, suggesting that TGF-beta acts as a tumor suppressor in mouse models of cancer. A screen to identify agents that potentiate TGF-beta-induced growth arrest demonstrated that the potential anticancer agent rapamycin cooperated with TGF-beta to induce growth arrest in multiple cell lines. Rapamycin also augmented the ability of TGF-beta to inhibit the proliferation of E2F1-, c-Myc-, and (V12)H-Ras-transformed cells, even though these cells were insensitive to TGF-beta-mediated growth arrest in the absence of rapamycin. Rapamycin potentiation of TGF-beta-induced growth arrest could not be explained by increases in TGF-beta receptor levels or rapamycin-induced dissociation of FKBP12 from the TGF-beta type I receptor. Significantly, TGF-beta and rapamycin cooperated to induce growth inhibition of human carcinoma cells that are resistant to TGF-beta-induced growth arrest, and arrest correlated with a suppression of Cdk2 kinase activity. Inhibition of Cdk2 activity was associated with increased binding of p21 and p27 to Cdk2 and decreased phosphorylation of Cdk2 on Thr(160). Increased p21 and p27 binding to Cdk2 was accompanied by decreased p130, p107, and E2F4 binding to Cdk2. Together, these results indicate that rapamycin and TGF-beta cooperate to inhibit the proliferation of nontransformed cells and cancer cells by acting in concert to inhibit Cdk2 activity.
转化生长因子β（TGF-β）可诱导大多数未转化的上皮细胞系发生细胞周期停滞。相比之下，许多人类癌症对TGF-β的生长抑制作用具有抗性。TGF-β的过表达会抑制肿瘤发生，而TGF-β信号的缺失则会加速肿瘤发生，这表明在癌症小鼠模型中TGF-β起着肿瘤抑制因子的作用。一项旨在鉴定增强TGF-β诱导的生长停滞的药物的筛选实验表明，潜在的抗癌药物雷帕霉素与TGF-β协同作用，可在多个细胞系中诱导生长停滞。雷帕霉素还增强了TGF-β抑制E2F1、c-Myc和（V12）H-Ras转化细胞增殖的能力，尽管在没有雷帕霉素的情况下这些细胞对TGF-β介导的生长停滞不敏感。雷帕霉素对TGF-β诱导的生长停滞的增强作用无法通过TGF-β受体水平的增加或雷帕霉素诱导的FKBP12从TGF-βI型受体上解离来解释。重要的是，TGF-β和雷帕霉素协同作用可诱导对TGF-β诱导的生长停滞具有抗性的人类癌细胞发生生长抑制，且这种停滞与Cdk2激酶活性的抑制相关。Cdk2活性的抑制与p21和p27与Cdk2的结合增加以及Cdk2在苏氨酸160位点的磷酸化减少有关。p21和p27与Cdk2结合的增加伴随着p130、p107和E2F4与Cdk2结合的减少。总之，这些结果表明雷帕霉素和TGF-β通过协同抑制Cdk2活性来抑制未转化细胞和癌细胞的增殖。
