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The secoiridoid glycoside Gentiopicroside is a USP22 inhibitor with potent antitumor immunotherapeutic activity.
Lu, Weiyuan; Chu, Peng; Tang, Amy; Si, Ligang; Fang, Deyu.
Afiliación
  • Lu W; Department of Pathology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Avenue, Chicago, IL 60611, USA; Department of Pediatrics, The Sixth Affiliated Hospital of Harbin Medical University, Heilongjiang 150028, China.
  • Chu P; College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China.
  • Tang A; Department of Pathology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Avenue, Chicago, IL 60611, USA.
  • Si L; Department of Pediatrics, The Sixth Affiliated Hospital of Harbin Medical University, Heilongjiang 150028, China.
  • Fang D; Department of Pathology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Avenue, Chicago, IL 60611, USA. Electronic address: fangd@northwestern.edu.
Biomed Pharmacother ; 177: 116974, 2024 Aug.
Article en En | MEDLINE | ID: mdl-38968798
ABSTRACT
Over the past decade, immunotherapies have brought about significant changes in how we approach the treatment of various solid tumors and blood-related cancers. However, the effectiveness of checkpoint blockade therapy has been constrained to a rate of under 30 %. A significant challenge in the realm of tumor immunotherapy revolves around comprehending the mechanisms through which regulatory T (Treg) cells induce immunosuppression. We have recently discovered that USP22 (ubiquitin-specific peptidase 22) a deubiquitinating enzyme that is increased in various tumors, is an oncogene and controls Treg immune suppressive activity for tumor evasion, providing a rationale for USP22 targeting to achieve both onco- and immuno-therapeutic efficacies. Herein, we identified the traditional Chinese secoiridoid compound gentiopicroside as a USP22 inhibitor. Gentiopicroside treatment decreased the forkhead box P3 (Foxp3) expression, which subsequently reduced Treg immune suppressive activity. Treatment of cancer cells by gentiopicroside resulted in an increase in histone 2B monoubiquitination (H2Bub) in a USP22-dependent manner and a decrease in programmed cell death ligand 1 (PD-L1) expression, both of which are known as USP22-specific substrates. Docking and molecular dynamic simulation revealed that gentiopicroside stably binds to USP22 catalytic pocket, supporting that gentiopicroside is a USP22 inhibitor. Importantly, administration of gentiopicroside to mice significantly inhibited the growth of syngenetic lung adenocarcinoma. Further analysis of intratumoral immune cells revealed a dramatic increase CD8+ T cell production of IFN-γ and granzyme B (GZMB), confirming that gentiopicroside enhances antitumor immunity. Our study revealed that gentiopicroside is a USP22-specific inhibitor with potent antitumor therapeutic potentials.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Linfocitos T Reguladores / Ubiquitina Tiolesterasa / Glucósidos Iridoides / Inmunoterapia Límite: Animals / Humans Idioma: En Revista: Biomed Pharmacother Año: 2024 Tipo del documento: Article Pais de publicación: Francia
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Linfocitos T Reguladores / Ubiquitina Tiolesterasa / Glucósidos Iridoides / Inmunoterapia Límite: Animals / Humans Idioma: En Revista: Biomed Pharmacother Año: 2024 Tipo del documento: Article Pais de publicación: Francia