Apoptosis resistance of senescent human fibroblasts is correlated with the absence of nuclear IGFBP‐3

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Abstract
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.