Targeting the Ubiquitin Signaling Cascade in Tumor Microenvironment for Cancer Therapy

Liu, Qi; Aminu, Bayonle; Roscow, Olivia; Zhang, Wei

doi:10.3390/ijms22020791

Cited by 27 publications

(21 citation statements)

References 131 publications

(245 reference statements)

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“…MDM2 inhibitors work by inhibiting the E3 ligase activity of MDM2 and interfering with the MDM2-p53 interaction [ 162 , 211 ]. Many MDM2 inhibitors, with unique structure, high efficiency, and no peptides, have been successfully designed and developed [ 162 ], including Nutlin-3a [ 170 ], HLI98 [ 171 ], MEL23, and MEL24 [ 172 ].…”

Section: Therapeutic Targeting Of E3 Ligases In Cancer Immunotherapymentioning

confidence: 99%

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

Chi

Cha

et al. 2021

Cells

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Cancer immunotherapies, including immune checkpoint inhibitors and immune pathway–targeted therapies, are promising clinical strategies for treating cancer. However, drug resistance and adverse reactions remain the main challenges for immunotherapy management. The future direction of immunotherapy is mainly to reduce side effects and improve the treatment response rate by finding new targets and new methods of combination therapy. Ubiquitination plays a crucial role in regulating the degradation of immune checkpoints and the activation of immune-related pathways. Some drugs that target E3 ubiquitin ligases have exhibited beneficial effects in preclinical and clinical antitumor treatments. In this review, we discuss mechanisms through which E3 ligases regulate tumor immune checkpoints and immune-related pathways as well as the opportunities and challenges for integrating E3 ligases targeting drugs into cancer immunotherapy.

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Section: Therapeutic Targeting Of E3 Ligases In Cancer Immunotherapymentioning

confidence: 99%

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

Chi

Cha

et al. 2021

Cells

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“…These UbVs can inhibit HECT, monomeric RING/Ubox, or multi-subunit SCF RING E3 ligases or deubiquitinases. Alternatively, they can activate HECT or homodimeric RING E3 ligases (Ernst et al, 2013;Liu et al, 2021). In the case of RING/Ubox E3 ligases, inhibition occurs via blocking the E3ubiquitin binding surface and activation occurs via stabilization of the E2-ubiquitin interaction (Gabrielsen et al, 2017 demonstrated that with HECT E3 ligases, the UbV-based inhibition is due to blocking the E2 binding site, whereas activation is observed in response to UbV binding to the N-lobe exosite.…”

Section: Phage Display Assays To Identify Novel E3 Ligase Ligands or Substratesmentioning

confidence: 99%

Exploration of Aberrant E3 Ligases Implicated in Alzheimer’s Disease and Development of Chemical Tools to Modulate Their Function

Potjewyd

Axtman

2021

Front. Cell. Neurosci.

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The Ubiquitin Proteasome System (UPS) is responsible for the degradation of misfolded or aggregated proteins via a multistep ATP-dependent proteolytic mechanism. This process involves a cascade of ubiquitin (Ub) transfer steps from E1 to E2 to E3 ligase. The E3 ligase transfers Ub to a targeted protein that is brought to the proteasome for degradation. The inability of the UPS to remove misfolded or aggregated proteins due to UPS dysfunction is commonly observed in neurodegenerative diseases, such as Alzheimer’s disease (AD). UPS dysfunction in AD drives disease pathology and is associated with the common hallmarks such as amyloid-β (Aβ) accumulation and tau hyperphosphorylation, among others. E3 ligases are key members of the UPS machinery and dysfunction or changes in their expression can propagate other aberrant processes that accelerate AD pathology. The upregulation or downregulation of expression or activity of E3 ligases responsible for these processes results in changes in protein levels of E3 ligase substrates, many of which represent key proteins that propagate AD. A powerful way to better characterize UPS dysfunction in AD and the role of individual E3 ligases is via the use of high-quality chemical tools that bind and modulate specific E3 ligases. Furthermore, through combining gene editing with recent advances in 3D cell culture, in vitro modeling of AD in a dish has become more relevant and possible. These cell-based models of AD allow for study of specific pathways and mechanisms as well as characterization of the role E3 ligases play in driving AD. In this review, we outline the key mechanisms of UPS dysregulation linked to E3 ligases in AD and highlight the currently available chemical modulators. We present several key approaches for E3 ligase ligand discovery being employed with respect to distinct classes of E3 ligases. Where possible, specific examples of the use of cultured neurons to delineate E3 ligase biology have been captured. Finally, utilizing the available ligands for E3 ligases in the design of proteolysis targeting chimeras (PROTACs) to degrade aberrant proteins is a novel strategy for AD, and we explore the prospects of PROTACs as AD therapeutics.

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“…Ubiquitination is a post-translational medication pathway involved in wide range of cellular functions, including autophagy, immune response, and DNA damage response ( Shaid et al, 2013 ). During ubiquitination, ubiquitin protein is attached to target proteins through catalysis pathway mediated by E1 ubiquitin-activating enzymes, E2 ubiquitin-conjugating enzymes and E3 ubiquitin ligases ( Liu et al, 2021 ). UAE and UBA6, both referred as E1 enzymes, are known to initiate ubiquitin conjugation by regulating cellular ubiquitin-charging ( Jin et al, 2007 ).…”

Section: Introductionmentioning

confidence: 99%

Overexpression of ABCG2 Confers Resistance to MLN7243, a Ubiquitin-Activating Enzyme (UAE) Inhibitor

Yang

Wang

et al. 2021

Front. Cell Dev. Biol.

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Overexpression of ATP-binding cassette transporter superfamily G member 2 (ABCG2), is known as a major mechanism mediating multidrug resistance (MDR) in cancer cells. MLN7243 is a small-molecule ubiquitin activating enzyme inhibitor currently under clinical investigation. The aim of the current study is to determine if MLN7243 is a substrate of MDR-related ABCG2 transporter. Our results showed that cancer cells overexpressing ABCG2 transporter were resistant to MLN7243 compared to the parental cells, while knockout of ABCG2 gene or pharmacological inhibition of ABCG2 efflux function completely reversed the drug resistance. Unexpectedly, the endogenous low expression of ABCG2 is sufficient to confer cancer cells resistance to MLN7243. The ABCG2 ATPase assay and HPLC assay suggested that MLN7243 can significantly stimulate ABCG2 ATPase activity and be pumped out from ABCG2-overexpressing cells by ABCG2. The docking analysis also implied that MLN7243 binds to ABCG2 drug-binding pocket with optimal binding affinity. However, MLN7243 did not competitively inhibit the efflux of other ABCG2 substrate drugs, indicating it may not serve as an MDR reversal agent. In conclusion, our study provides direct in vitro evidence to show that MLN7243 is a potent ABCG2 substrate. If our results can be translated to humans, it suggests that combining MLN7243 with ABCG2 inhibitors may enhance the anticancer efficacy for patients with high tumor ABCG2 level.

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Targeting the Ubiquitin Signaling Cascade in Tumor Microenvironment for Cancer Therapy

Cited by 27 publications

References 131 publications

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

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

Exploration of Aberrant E3 Ligases Implicated in Alzheimer’s Disease and Development of Chemical Tools to Modulate Their Function

Overexpression of ABCG2 Confers Resistance to MLN7243, a Ubiquitin-Activating Enzyme (UAE) Inhibitor

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