Abstract
The accumulation of senescent cells (SnCs) is a causal factor of various age‐related diseases as well as some of the side effects of chemotherapy. Pharmacological elimination of SnCs (senolysis) has the potential to be developed into novel therapeutic strategies to treat these diseases and pathological conditions. Here we show that ubiquitin‐specific peptidase 7 (USP7) is a novel target for senolysis because inhibition of USP7 with an inhibitor or genetic depletion of USP7 by RNA interference induces apoptosis selectively in SnCs. The senolytic activity of USP7 inhibitors is likely attributable in part to the promotion of the human homolog of mouse double minute 2 (MDM2) ubiquitination and degradation by the ubiquitin–proteasome system. This degradation increases the levels of p53, which in turn induces the pro‐apoptotic proteins PUMA, NOXA, and FAS and inhibits the interaction of BCL‐XL and BAK to selectively induce apoptosis in SnCs. Further, we show that treatment with a USP7 inhibitor can effectively eliminate SnCs and suppress the senescence‐associated secretory phenotype (SASP) induced by doxorubicin in mice. These findings suggest that small molecule USP7 inhibitors are novel senolytics that can be exploited to reduce chemotherapy‐induced toxicities and treat age‐related diseases.
Highlights
Cellular senescence is a phenomenon by which replication-competent cells cease to divide after extensive replication or exposure to stress (Hayflick et al, 1965; Childs et al, 2017)
Our results show that inhibition of ubiquitin-specific peptidase 7 (USP7) by a small molecule or genetic depletion can selectively induce apoptosis in several types of senescent cells (SnCs) at least in part via restoring p53 activity, which in turn induces the pro-apoptotic proteins PUMA, NOXA, and FAS and inhibits the interaction of BCL-XL and BAK because SnCs are more sensitive to the perturbation of mitochondrial apoptotic pathways than non-SnCs (Chang et al, 2016; Yosef et al, 2016; Zhu et al, 2017)
We show that treatment with a USP7 inhibitor can effectively eliminate SnCs and suppress the senescence-associated secretory phenotype (SASP) induced by doxorubicin in mice without causing changes in blood cell counts and loss of body weight
Summary
Cellular senescence is a phenomenon by which replication-competent cells cease to divide after extensive replication or exposure to stress (Hayflick et al, 1965; Childs et al, 2017). We show that treatment with a USP7 inhibitor can effectively eliminate SnCs and suppress the SASP induced by doxorubicin in mice without causing changes in blood cell counts and loss of body weight These findings suggest that small molecule USP7 inhibitors are novel senolytics that can be exploited to reduce chemotherapy-induced toxicities and treat age-related diseases. P5091 had no significant effect on the interaction between BCL-2 and p53, nor on the interactions between BCL-2 and BAX or BAK (Figure 3h and i) These findings suggest that USP7 inhibition selectively induces SnC apoptosis at least in part by increasing p53 translocation to mitochondria and its interaction with BCL-XL, since SnCs are more dependent on BCL-2 family proteins for survival compared to non-SnCs (Chang et al, 2016; Yosef et al, 2016; Zhu et al, 2016). Kidneys from DOX-treated mice expressed increased levels of mRNAs
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