USP7 inhibitor P5091 inhibits Wnt signaling and colorectal tumor growth

An, Tao; Gong, Yingchun; Xue, Li; Kong, Lingmei; Ma, Ping; Gong, Liang; Zhu, Hui; Yu, Chunlei; Liu, Jianmei; Zhou, Hongyu; Mao, Bingyu; Li, Yan

doi:10.1016/j.bcp.2017.02.011

Cited by 98 publications

(97 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A serious of inhibitors targeting USP7 was evaluated in vitro and in vivo studies . In which, P5091 was identified as a specific inhibitor of USP7 and showed a promising anti‐cancer effect in several tumors . Here, we found that inactivation of USP7 using P5091 effectively inhibited esophageal cancer cell growth in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 82%

“…It is still important to understand the mechanistic basis for ESCC progression and to develop novel anti‐ESCC strategies. Recent reports showed that deubiquitinase USP7 play an important role in various pathways and involved in a variety of pathophysiological processes, including cancer . USP7 was expressed abnormally and correlated with tumor's prognosis in a tumor‐specific manner .…”

Section: Discussionmentioning

confidence: 99%

“…In multiple myeloma cells, P5091 treatment inhibited cell proliferation and induced apoptosis in a p53‐independent manner . Additionally, P5091 could inhibit colon cancer cells growth by inhibiting Wnt signaling . In neuroendocrine tumors of the lung, P5091 enhanced the drug sensitivity by downregulating the expression of CCDC6 to regulate the DNA repair .…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Targeting the overexpressed USP7 inhibits esophageal squamous cell carcinoma cell growth by inducing NOXA‐mediated apoptosis

Zhang

Sha

et al. 2018

Molecular Carcinogenesis

View full text Add to dashboard Cite

Increasing evidence suggests that deubiquitinase USP7 participates in tumor progression by various mechanisms and serves as a potential therapeutic target. However, its expression and role in esophageal cancer remains elusive; the anti-cancer effect by targeting USP7 still needs to be investigated. Here, we reported that USP7 was overexpressed in esophageal squamous cell carcinoma (ESCC) tissues compared with adjacent tissues, implying that USP7 was an attractive anticancer target of ESCC. Pharmaceutical or genetic inactivation of USP7 inhibited esophageal cancer cells growth in vitro and in vivo and induced apoptosis. Mechanistically, inhibition of USP7 accumulated poly-ubiquitinated proteins, activated endoplasmic reticulum stress, and increased expression of ATF4, which transcriptionally upregulated expression of NOXA and induced NOXA-mediated apoptosis. These results provide an evidence for clinical investigation of USP7 inhibitors for the treatment of ESCC.

show abstract

Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Targeting the overexpressed USP7 inhibits esophageal squamous cell carcinoma cell growth by inducing NOXA‐mediated apoptosis

Zhang

Sha

et al. 2018

Molecular Carcinogenesis

View full text Add to dashboard Cite

show abstract

“…Therefore, it is possible that USP7 inhibition may induce SnC apoptosis not only via a p53‐dependent manner but also through a p53‐independent mechanism. It has been shown previously that USP7 inhibition can induce apoptosis in various cancer cells via restoration of PTEN nuclear pool (Carrà et al, ), inhibition of Wnt signaling (An et al, ), and induction of oxidative and endoplasmic reticulum stress (Lee et al, ). However, whether any of these mechanisms contribute to USP7 inhibition‐induced SnC apoptosis has yet to be determined.…”

Section: Discussionmentioning

confidence: 97%

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

et al. 2020

Aging Cell

View full text Add to dashboard Cite

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.

show abstract

“…It was shown to be capable of inducing apoptosis and overcoming bortezomib resistance in multiple myeloma [22]. Further studies in other cancer types revealed that P5091 can down-regulate CCDC6, sensitize lung neuroendocrine cancer to PARP inhibitors, and deter Wnt signalling to repress colorectal tumour growth [36, 37]. …”

Section: Discussionmentioning

confidence: 99%

The USP7 Inhibitor P5091 Induces Cell Death in Ovarian Cancers with Different P53 Status

Wang

Zhang

Wang

et al. 2017

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Ovarian cancer is often diagnosed at later stages with poor prognosis. Recent studies have associated the expression of deubiquitylase USP7 with the survival of ovarian cancers. Being a cysteine protease, USP7 could become a target for pharmacological intervention. Therefore, in this study, we assessed the influence of its inhibitor P5091 on ovarian cancer cells. Methods: Ovarian cancer cells were treated with P5091, and cell proliferation was measured with MTT assay; cell morphology was inspected under a phase-contrast microscope; cell cycle and cell death were examined by flow cytometry. To gain mechanistic insights into its effects, immunoblotting was performed to detect USP7, HDM2, p53, p21, apoptosis and autophagy related proteins. Results: P5091 effectively suppressed the growth of ovarian cancer cells, caused cell cycle blockage, and induced necrosis and apoptosis with more severe phenotypes observed in HeyA8 cells with wild-type p53 than in OVCAR-8 cells with mutant p53. P5091 also prompted autophagy, with more efficient p62 degradation in HeyA8. Conclusion: P5091 shows efficacy in suppressing ovarian cancers harbouring wild-type and mutant p53. Its effects seemed to be enhanced by wild-type p53. The potency of this USP7 inhibitor also correlated with autophagy to some extent. Therefore, the pharmacological targeting of USP7 may serve as a potential therapeutic strategy and warrants further investigation.

show abstract

USP7 inhibitor P5091 inhibits Wnt signaling and colorectal tumor growth

Cited by 98 publications

References 46 publications

Targeting the overexpressed USP7 inhibits esophageal squamous cell carcinoma cell growth by inducing NOXA‐mediated apoptosis

Targeting the overexpressed USP7 inhibits esophageal squamous cell carcinoma cell growth by inducing NOXA‐mediated apoptosis

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

The USP7 Inhibitor P5091 Induces Cell Death in Ovarian Cancers with Different P53 Status

Contact Info

Product

Resources

About