Apoptosis resistance of senescent human fibroblasts is correlated with the absence of nuclear IGFBP-3
Apoptosis resistance of senescent human fibroblasts is correlated with the absence of nuclear IGFBP-3
复制标题
DOI：
10.1111/j.1474-9726.2005.00180.x
复制
发表时间：
2005-12-01
期刊：
影响因子：
7.8
通讯作者：
Jansen-Dürr, P
中科院分区：
文献类型：
--
作者：
Hampel, B;Wagner, M;Jansen-Dürr, P
在许多物种中，通过胰岛素/IGF轴的信号传导在决定衰老速度方面起着重要作用。IGF结合蛋白（igfbp）在高等生物体内调节IGF通路。IGFBP-3在衰老的人成纤维细胞的条件培养基中积累，表明它可能有助于衰老表型。IGFBP-3能够靶向细胞内凋亡调节因子，包括核转录因子，从而增强肿瘤细胞的凋亡细胞死亡。衰老成纤维细胞对凋亡具有高度抗性，表明IGFBP-3不能诱导这种细胞类型的凋亡；然而，衰老细胞抗凋亡的机制尚不清楚。为了解决这个问题，我们研究了衰老成纤维细胞中IGFBP-3的产生和细胞内定位。虽然IGFBP-3在衰老成纤维细胞中高度过表达，但在衰老成纤维细胞的细胞核中未检测到IGFBP-3。在肿瘤细胞中，IGFBP-3可以通过内吞作用被内化，这被认为是IGFBP-3在细胞内发挥功能的先决条件，也可能是其转运到细胞核的先决条件；我们在这里表明，IGFBP-3的内吞摄取不会发生在衰老的人类成纤维细胞中。这与这些细胞的内吞活性普遍下降有关，如模型底物转铁蛋白所示。这些数据与IGFBP-3在衰老成纤维细胞条件培养基中的积累导致这些细胞生长停滞的模型一致，而不能内吞IGFBP-3和缺乏核IGFBP-3可能有助于衰老人成纤维细胞的细胞凋亡抵抗。
Signaling through the insulin/IGF axis plays a major role in determining the rate of aging in many species. IGF-binding proteins (IGFBPs) modulate the IGF pathway in higher organisms. IGFBP-3 accumulates in conditioned medium of senescent human fibroblasts, suggesting that it may contribute to the senescent phenotype. IGFBP-3 can enhance apoptotic cell death in tumor cells due to its ability to target intracellular regulators of apoptosis, including nuclear transcription factors. Senescent fibroblasts are highly resistant to apoptosis, suggesting that IGFBP-3 fails to induce apoptosis in this cell type; however, mechanisms of apoptosis resistance in senescent cells are poorly understood. To address this question, we studied the production and intracellular localization of IGFBP-3 in senescent fibroblasts. Whereas IGFBP-3 is highly overexpressed by senescent fibroblasts, IGFBP-3 was not detectable in the nucleus of senescent fibroblasts. In tumor cells, IGFBP-3 can be internalized by endocytosis, which is considered as a prerequisite for the intracellular functions of IGFBP-3 and probably also for its transport to the nucleus; we show here that endocytotic uptake of IGFBP-3 does not occur in senescent human fibroblasts. This is correlated with a generally decreased endocytotic activity of these cells, as shown with the model substrate transferrin. The data are consistent with a model where IGFBP-3 accumulation in conditioned medium of senescent fibroblasts contributes to growth arrest of these cells, whereas the failure to endocytose IGFBP-3 and the absence of nuclear IGFBP-3 may contribute to the well-established apoptosis resistance of senescent human fibroblasts.