Small-molecule inhibitors of USP7 induce apoptosis through oxidative and endoplasmic reticulum stress in cancer cells

Lee, Gibok; Oh, Taek-In; Um, Ki Bum; Yoon, Hyeshin; Son, Jaekyoung; Kim, Byeong Mo; Kim, Hong-Il; Kim, Hackyoung; Kim, Young Jun; Lee, Chang‐Soo; Lim, Ji-Hong

doi:10.1016/j.bbrc.2016.01.021

Cited by 33 publications

(37 citation statements)

References 34 publications

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“…Here, we found that inactivation of USP7 using P5091 effectively inhibited esophageal cancer cell growth in vitro and in vivo. At the same time, we found that different cell lines exhibited slightly different sensitivity to P5091, which was in accordance with previous reports . Our results found that the expression of USP7 was cell‐dependent (unpublished data).…”

Section: Discussionsupporting

confidence: 93%

“…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%

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

Zhang

Sha

et al. 2018

Molecular Carcinogenesis

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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.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

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

Zhang

Sha

et al. 2018

Molecular Carcinogenesis

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“…Recently a few inhibitors have been developed to specifically target USP7 with promising results in different cancer models [17, 44–50]. USP7 inhibitor P5091 was shown to exhibit impressive properties for the treatment of Multiple Myeloma (MM) [17].…”

Section: Resultsmentioning

confidence: 99%

Therapeutic inhibition of USP7-PTEN network in chronic lymphocytic leukemia: a strategy to overcome TP53 mutated/deleted clones

et al. 2017

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Chronic Lymphocytic Leukemia (CLL) is a lymphoproliferative disorder with either indolent or aggressive clinical course. Current treatment regiments have significantly improved the overall outcomes even if higher risk subgroups - those harboring TP53 mutations or deletions of the short arm of chromosome 17 (del17p) - remain highly challenging. In the present work, we identified USP7, a known de-ubiquitinase with multiple roles in cellular homeostasis, as a potential therapeutic target in CLL. We demonstrated that in primary CLL samples and in CLL cell lines USP7 is: i) over-expressed through a mechanism involving miR-338-3p and miR-181b deregulation; ii) functionally activated by Casein Kinase 2 (CK2), an upstream interactor known to be deregulated in CLL; iii) effectively targeted by the USP7 inhibitor P5091. Treatment of primary CLL samples and cell lines with P5091 induces cell growth arrest and apoptosis, through the restoration of PTEN nuclear pool, both in TP53-wild type and -null environment. Importantly, PTEN acts as the main tumor suppressive mediator along the USP7-PTEN axis in a p53 dispensable manner. In conclusion, we propose USP7 as a new druggable target in CLL.

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“…43,44 The H 2 O 2 and O 2 -levels after treatment with epirubicin or liposomal epirubicin were significantly higher than those with hepcidin 2-3 or liposomal hepcidin 2-3 alone ( Figure 3A …”

Section: Pegylated Liposomal Epirubicin and Hepcidin 2-3 Enhanced Rosmentioning

confidence: 98%

Cationic PEGylated liposomes incorporating an antimicrobial peptide tilapia hepcidin 2–3: an adjuvant of epirubicin to overcome multidrug resistance in cervical cancer cells

Juang¹,

Lee²,

Lin³

et al. 2016

IJN

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Small-molecule inhibitors of USP7 induce apoptosis through oxidative and endoplasmic reticulum stress in cancer cells

Cited by 33 publications

References 34 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

Therapeutic inhibition of USP7-PTEN network in chronic lymphocytic leukemia: a strategy to overcome TP53 mutated/deleted clones

Cationic PEGylated liposomes incorporating an antimicrobial peptide tilapia hepcidin 2–3: an adjuvant of epirubicin to overcome multidrug resistance in cervical cancer cells

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Small-molecule inhibitors of USP7 induce apoptosis through oxidative and endoplasmic reticulum stress in cancer cells

Cited by 33 publications

References 34 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

Therapeutic inhibition of USP7-PTEN network in chronic lymphocytic leukemia: a strategy to overcome TP53 mutated/deleted clones

Cationic PEGylated liposomes incorporating an antimicrobial peptide tilapia hepcidin 2&ndash;3: an adjuvant of epirubicin to overcome multidrug resistance in cervical cancer cells

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Cationic PEGylated liposomes incorporating an antimicrobial peptide tilapia hepcidin 2–3: an adjuvant of epirubicin to overcome multidrug resistance in cervical cancer cells