Survivin expression increases during aging and enhances the resistance of aged human fibroblasts to genotoxic stress

Abstract

Survivin, an important anti-apoptotic protein, is highly expressed in most cancers, which generally arise in cells of older individuals. We have shown here accumulation of survivin and phospho-survivin in aged normal human skin fibroblasts and mice organs. This age-related accumulation of survivin was due to protein stabilization through association with the molecular chaperone Hsp90 protein, which was also up-regulated during aging. Interestingly, Hsp90 binds preferentially to phospho-survivin, which explains its higher stability. In addition, we provide clear evidence that aged cells exhibit apoptosis resistance when challenged with UV light, cisplatin, γ-rays or H 2 O 2 as compared to their younger counterparts. In response to γ-rays and H 2 O 2 , the levels of Bcl-2 and both forms of survivin were upregulated in old cells, but not in their corresponding young ones. This repression of survivin and phosphosurvivin in young cells is p53 dependent. Importantly, survivin inhibition/down-regulation with flavopiridol or specific shRNAs increased the apoptotic response of old fibroblasts to various genotoxic agents, and restored the pro-apoptotic Bax/Bcl2 ratio and the increase in the levels of cleaved caspase-3 and PARP in old cells. These results show the role of survivin in the age-dependent resistance of human fibroblasts, and provide new insights into the molecular mechanisms that underlie the complex relationship between aging, apoptosis, and cancer.

Reversal of Persistent Fibrosis in Aging by Targeting Nox4-Nrf2 Redox Imbalance

“…Our studies implicate apoptosis resistance as a key mechanism by which myofibroblast senescence contributes to persistent fibrosis in aging. Indeed, studies in our laboratory and others support the acquisition of an apoptosis-resistant phenotype in senescent fibroblasts, in part related to higher expression of Bcl-2 (36,37). Our current findings of high expression of Bcl-2 in fibroblasts isolated from aged mice subjected to bleomycin injury are consistent with this as one mechanism of apoptosis resistance.…”

The mitomiR/Bcl-2 axis affects mitochondrial function and autophagic vacuole formation in senescent endothelial cells

“…Interestingly, Survivin siRNA had not yet been screened to develop senolytic molecules [ 44 – 46 ]. However, Al-Khalaf et al reported that its inhibition with flavopiridol or specific shRNAs increases the apoptotic response of senescent fibroblast to various stressors [ 48 ]. As a result, sHUVECs are more resistant to apoptosis despite i) Bcl-2 downregulation and ii) exhibition of several characteristics of dysfunctional cells in which the early stages of programmed cell death have been activated, like ROS production, a significant increase in mPTP opening, and slight casp-3 activity, all findings that may be the result of Bcl-2 downregulation.…”

Why Senescent Cells Are Resistant to Apoptosis: An Insight for Senolytic Development

“…Al-Khalaf et al found that survivin and phospho-survivin were accumulated in aged normal human skin fibroblasts and mice organs, which may be attributable to HSP90-mediated stabilization of survivin. Inhibition of survivin by flavopiridol or shRNAs increased the apoptotic response of old fibroblasts to various genotoxic agents by restoring the pro-apoptotic Bax/Bcl-2 ratio and increasing the levels of cleaved caspase-3 and PARP ( Al-Khalaf and Aboussekhra, 2013 ). Another study indicated that nuclear accumulation of Yes-associated protein (YAP) could promote the survival of senescent tumor cells by increasing the expression of survivin ( Ma et al, 2016 ).…”