Potential of E3 Ubiquitin Ligases in Cancer Immunity: Opportunities and Challenges

Ye, Peng; Chi, Xiaoxia; Cha, Jong-Ho; Luo, Shahang; Yang, Guanghui; Yan, Xiuwen; Yang, Wenhao

doi:10.3390/cells10123309

Cited by 28 publications

(23 citation statements)

References 282 publications

(375 reference statements)

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“…Analogously, RNF5 activation slows the proliferation of melanoma cells, which, irrespective of their oncogenic background, depend on glutamine to grow [ 45 ]. Another important aspect to be considered is that E3 ubiquitin ligases, rather than a direct effect on tumor cells, play a crucial role in regulating anti-tumor immune responses by the degradation of immune checkpoints and the activation of immune-related pathways [ 46 ] However, the specific role of RNF5 in the latter phenomena has not yet been defined. Notably, rnf5 −/− mice present an enhanced antitumor response, which is coupled with greater recovery and function of CD8 + lymphocytes in melanoma tumors [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

Targeting of Ubiquitin E3 Ligase RNF5 as a Novel Therapeutic Strategy in Neuroectodermal Tumors

Principi

Sondo

Bianchi

et al. 2022

Cancers

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RNF5, an endoplasmic reticulum (ER) E3 ubiquitin ligase, participates to the ER-associated protein degradation guaranteeing the protein homeostasis. Depending on tumor model tested, RNF5 exerts pro- or anti-tumor activity. The aim of this study was to elucidate the controversial role of RNF5 in neuroblastoma and melanoma, two neuroectodermal tumors of infancy and adulthood, respectively. RNF5 gene levels are evaluated in publicly available datasets reporting the gene expression profile of melanoma and neuroblastoma primary tumors at diagnosis. The therapeutic effect of Analog-1, an RNF5 pharmacological activator, was investigated on in vitro and in vivo neuroblastoma and melanoma models. In both neuroblastoma and melanoma patients the high expression of RNF5 correlated with a better prognostic outcome. Treatment of neuroblastoma and melanoma cell lines with Analog-1 reduced cell viability by impairing the glutamine availability and energy metabolism through inhibition of F1Fo ATP-synthase activity. This latter event led to a marked increase in oxidative stress, which, in turn, caused cell death. Similarly, neuroblastoma- and melanoma-bearing mice treated with Analog-1 showed a significant delay of tumor growth in comparison to those treated with vehicle only. These findings validate RNF5 as an innovative drug target and support the development of Analog-1 in early phase clinical trials for neuroblastoma and melanoma patients.

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Section: Discussionmentioning

confidence: 99%

Targeting of Ubiquitin E3 Ligase RNF5 as a Novel Therapeutic Strategy in Neuroectodermal Tumors

Principi

Sondo

Bianchi

et al. 2022

Cancers

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“…Notably, blocking the SIRP-α-CD47 signaling pathway in combination with chemoradiotherapy can further improve the antitumor therapeutic effect [ 19 ]. Moreover, targeting E3-ligase-mediated CD47 degradation to boost anticancer immunity also has been discussed [ 223 ]. The above findings suggest that blocking the SIRP-α-CD47 signaling pathway with monoclonal antibodies or small-molecule inhibitors can effectively block CSC–TAM interaction, thereby inhibiting the progression of CSCs and reducing the tumor burden in vivo.…”

Section: Therapeutic Strategies Targeting Cscs and Tamsmentioning

confidence: 99%

Macrophages Are a Double-Edged Sword: Molecular Crosstalk between Tumor-Associated Macrophages and Cancer Stem Cells

Luo

Yang

et al. 2022

Biomolecules

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Cancer stem cells (CSCs) are a subset of highly tumorigenic cells in tumors. They have enhanced self-renewal properties, are usually chemo-radioresistant, and can promote tumor recurrence and metastasis. They can recruit macrophages into the tumor microenvironment and differentiate them into tumor-associated macrophages (TAMs). TAMs maintain CSC stemness and construct niches that are favorable for CSC survival. However, how CSCs and TAMs interact is not completely understood. An understanding on these mechanisms can provide additional targeting strategies for eliminating CSCs. In this review, we comprehensively summarize the reported mechanisms of crosstalk between CSCs and TAMs and update the related signaling pathways involved in tumor progression. In addition, we discuss potential therapies targeting CSC–TAM interaction, including targeting macrophage recruitment and polarization by CSCs and inhibiting the TAM-induced promotion of CSC stemness. This review also provides the perspective on the major challenge for developing potential therapeutic strategies to overcome CSC-TAM crosstalk.

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“…The drug development of E3 ligase has been a very challenging research hotspot in recent years. At present, antitumor drugs targeting E3 ligase are mainly divided into four categories according to their mechanism of action: E3 ligase targeted inhibitors, E3 ligase targeted agonists, proteolytic targeting chimeras (PROTACs), and molecular glues ( 159 ). Considering the complex and extensive life activities regulated by ubiquitination, blocking or activating E3 ligase to treat tumors may have adverse effects on other everyday life metabolic activities.…”

Section: Epigenetic In Tumor Progression and Metastasismentioning

confidence: 99%

Epigenetic modification regulates tumor progression and metastasis through EMT (Review)

et al. 2022

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Epigenetics is the study of heritable molecular determinants that are independent of phenotypic features. The epigenetic features include DNA methylation, histone modifications, non-coding RNAs, and chromatin remodeling. In multicellular organisms, the epigenetic state of a cell is critical in determining its differentiation status and its ability to perform its proper function. These processes are now well recognized as being a substantial factor in tumor progression and metastasis. The process through which epithelial cells acquire mesenchymal features is known as epithelial-mesenchymal transition (EMT). EMT is associated with tumorigenesis, invasion, metastasis, and resistance to therapy in cancer. In the present review, we examine the recent studies that demonstrate the biological role of epigenetics, in particular, DNA methylation, histone modifications, non-coding RNAs, and chromatin remodeling in tumor progression and metastasis by regulating EMT status, and we provide an overview of the current state of knowledge regarding the epigenetics involvement in tumor progression and metastasis. Because epigenetic changes can be reversed, learning more about their biological roles in EMT will not only help us better understand how cancer progresses and spreads, but it will also help us identify new ways to diagnose and treat human malignancy which is currently lacking in the clinical setting.

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Potential of E3 Ubiquitin Ligases in Cancer Immunity: Opportunities and Challenges

Cited by 28 publications

References 282 publications

Targeting of Ubiquitin E3 Ligase RNF5 as a Novel Therapeutic Strategy in Neuroectodermal Tumors

Targeting of Ubiquitin E3 Ligase RNF5 as a Novel Therapeutic Strategy in Neuroectodermal Tumors

Macrophages Are a Double-Edged Sword: Molecular Crosstalk between Tumor-Associated Macrophages and Cancer Stem Cells

Epigenetic modification regulates tumor progression and metastasis through EMT (Review)

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