Vasilcanu R, Vasilcanu D, Rosengren L, Natalishvili N, Sehat B, Yin S, Girnita A, Axelson M, Girnita L, Larsson O
Department of Oncology and Pathology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
Oncogene. 2008 Mar 6;27(11):1629-38. doi: 10.1038/sj.onc.1210797. Epub 2007 Sep 10.
The insulin-like growth factor 1 receptor (IGF-1R) is crucial for growth and survival of malignant cells. Experience in targeting IGF-1R in cancer models has shown that strategies promoting downregulation of the receptor are much more efficient in inducing apoptosis than those inhibiting the IGF-1R activity. Recently, we found that the cyclolignan picropodophyllin (PPP) inhibits phosphorylation of IGF-1R and activation of downstream signaling without interfering with the highly homologous insulin receptor (IR). Furthermore, PPP treatment caused strong regression of tumor grafts and prolonged survival of animals with systemic tumor disease. Here we demonstrate that PPP also downregulates the IGF-1R, whereas the IR and several other receptors were not affected. PPP-induced IGF-1R downregulation required expression of the MDM2 E3 ligase, which recently was found to ubiquitinate and cause degradation of the IGF-1R. In addition knockdown of beta-arrestin1, the adaptor molecule known to bridges MDM2 and IGF-1R, prevented downregulation of the receptor and significantly decreased PPP-induced cell death. All together these data suggest that PPP downregulates IGF-1R by interfering with the action of beta-arrestin1/MDM2 as well as the achieved receptor downregulation contributes to the apoptotic effect of PPP.
胰岛素样生长因子1受体（IGF-1R）对恶性细胞的生长和存活至关重要。在癌症模型中靶向IGF-1R的经验表明，促进该受体下调的策略在诱导细胞凋亡方面比抑制IGF-1R活性的策略更有效。最近，我们发现环木脂素类鬼臼苦素（PPP）可抑制IGF-1R的磷酸化和下游信号的激活，而不干扰高度同源的胰岛素受体（IR）。此外，PPP治疗可使肿瘤移植显著消退，并延长患有全身性肿瘤疾病动物的生存期。在此我们证明，PPP还可下调IGF-1R，而IR和其他几种受体未受影响。PPP诱导的IGF-1R下调需要MDM2 E3连接酶的表达，最近发现该酶可使IGF-1R泛素化并导致其降解。此外，β-抑制蛋白1（已知为连接MDM2和IGF-1R的衔接分子）的敲低可阻止受体下调，并显著降低PPP诱导的细胞死亡。所有这些数据表明，PPP通过干扰β-抑制蛋白1/MDM2的作用下调IGF-1R，并且所实现的受体下调有助于PPP的凋亡效应。
