Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity

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.

Senescent Cell Depletion Through Targeting BCL-Family Proteins and Mitochondria

“…Therefore, blocking the interaction between MDM2 and p53 can prevent p53 degradation, which increases p53 activity and deplete senescent cells. Most recently, He et al demonstrated that ubiquitinspecific peptidase 7 (USP7) inhibitor P5091 accelerated MDM2 ubiquitination and degradation, which in turn increased intracellular p53 expression and cleared senescent cells by activating cellular apoptosis (He et al, 2020a). The depletion of senescent cells by P5091 alleviated doxorubicin-induced SASP and renal toxicities in mice.…”

Senescence under appraisal: hopes and challenges revisited

“…Senolytics aim to induce death in senescent cells without affecting proliferating or quiescent cells, by targeting a wide range of vulnerabilities existing specifically in senescent cells. These include the increased expression of BCL anti-apoptotic proteins (navitoclax and other BH3-mimetics), the PI3K/AKT pathway (quercetin), ephrin receptors (dasatinib), lysosomal V-ATPase (bafilomycin A1, concanamycin A), Na + /K + ATPase (cardiac glycosides), MDM2/ p53 interaction (UBX0101), mTOR pathway (sertraline), oxidation resistance 1 (piperlongumine), USP7 protease (P22007), urokinase-type plasminogen activator receptor (CAR-T cells) and bromodomain and extra-terminal (BET) family proteins [66,128,[148][149][150][151][152][153][154]. General cytotoxic drugs like the antibiotic duocarmycin can also be converted into senolytics by addition of a galactose motif, creating a prodrug that is preferentially cleaved under high β-galactosidase expression, producing a targeted-delivery system for senescent cells [155].…”

Deubiquitinases: Modulators of Different Types of Regulated Cell Death

“…For example, USP7 promotes intrinsic apoptosis through p53, SUV39H1, and PLK1 and suppresses intrinsic apoptosis through MDM2 and Maf and suppresses the ER stress response. In addition, USP7 promotes extrinsic apoptosis by promoting RIPK1 activity and ferroptosis by suppressing SCL7A11 expression ( Figure 3 a) [ 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. BAP1 provides another example of the complex regulation of RCD through diverse mediators.…”

“…In addition to their roles in cancer, P5091 and P22077 induce p53-dependent apoptosis in senescent cells. P5091 alleviates the phenotypes of doxorubicin-induced senescence in mice by eliminating senescent cells and mitigating senescence-associated secretory phenotype (SASP) [ 33 ].…”