Roscovitine sensitizes breast cancer cells to TRAIL-induced apoptosis through a pleiotropic mechanism

肿瘤坏死因素(TNF ) 联系了导致 apoptosis ligand (TRAIL/APO2L ) 是在血缘的死亡受体的约会之上导致 apoptosis 的 TNF 基因总科的一个成员。当小道对正常房间相对无毒时，它有选择地在许多转变房间导致 apoptosis。不过，胸肿瘤房间对小道的效果特别地抵抗。这里，我们报导在有 cyclin 依赖的 kinase 禁止者 roscovitine 的联合，落后于的暴露在检验的小道抵抗的乳癌房间线的多数导致了显著 apoptosis。Roscovitine 便于小道导致死亡的发信号的复杂形成和 caspase-8 的激活。FLICE 禁止的蛋白质是的 cFLIP (L) 和 cFLIP 显著地下面调整的列在后面暴露到 roscovitine 并且，确实由 siRNA 的 cFLIP isoforms 击倒敏化的胸肿瘤房间到导致小道的 apoptosis。另外，我们证明 roscovitine 强烈在胸肿瘤房间压制了 Mcl-1 表示和起来调整的 E2F1 蛋白质层次。显著地，由 siRNA 的 Mcl-1 的 silencing 敏化胸肿瘤房间到导致小道的 apoptosis。而且，由减少的 siRNA 的 E2F1 蛋白质击倒在导致小道的 apoptosis 的 roscovitine 的敏化的效果。在摘要，我们的结果为 roscovitine 的 pro-apoptotic 影响揭示 pleitropic 机制，加亮它象在在有小道的联合的乳癌的一个反肿瘤代理人的潜力。

The tumor necrosis factor （TNF）-related apoptosis-inducing ligand （TRAIL/APO2L） is a member of the TNF gene superfamily that induces apoptosis upon engagement of cognate death receptors. While TRAIL is relatively non-toxic to normal cells, it selectively induces apoptosis in many transformed cells. Nevertheless, breast tumor cells are particularly resistant to the effects of TRAIL. Here we report that, in combination with the cyclin-dependent kinase inhibitor roscovitine, exposure to TRAIL induced marked apoptosis in the majority of TRAIL-resistant breast cancer cell lines examined. Roscovitine facilitated TRAIL death-inducing signaling complex formation and the activation of caspase-8. The cFLIPL and cFLIPs FLICE-inhibitory proteins were significantly down-regulated following exposure to roscovitine and, indeed, the knockdown of cFLIP isoforms by siRNA sensitized breast tumor cells to TRAIL-induced apoptosis. In addition, we demonstrate that roscovitine strongly suppressed Mcl-1 expression and up-regulated E2F1 protein levels in breast tumor ceils. Significantly, the silencing of Mci-1 by siRNA sensitized breast tumor cells to TRAIL-induced apoptosis. Furthermore, the knockdown of E2F1 protein by siRNA reduced the sensitizing effect of roscovitine in TRAIL-induced apoptosis. In summary, our results reveal a pleitropic mechanism for the pro-apoptotic influence of roscovitine, highlighting its potential as an antitumor agent in breast cancer in combination with TRAIL.