The characteristics and roles of β‐TrCP1/2 in carcinogenesis

Bi, Yanli; Cui, Di; Xiong, Xiufang; Zhao, Yongchao

doi:10.1111/febs.15585

Cited by 46 publications

(36 citation statements)

References 165 publications

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“…β-TrCP acts as a substrate receptor and constitutes an active SCF β-TrCP ligase with a scaffold protein cullin 1 (CUL1), a RING protein RBX1 and an adaptor protein SKP1 (37). β-TrCP plays a critical role in the regulation of various physiological and pathological processes, including signal transduction, cell cycle progression, cell migration, DNA damage response and tumorigenesis, by governing large amounts of key regulators for ubiquitination and proteasomal degradation (38). The results of previous studies have demonstrated that β-TrCP plays a vital role in carcinogenesis via promoting the degradation of its substrates, including oncoproteins and tumor suppressors (38).…”

Section: Discussionmentioning

confidence: 99%

“…β-TrCP plays a critical role in the regulation of various physiological and pathological processes, including signal transduction, cell cycle progression, cell migration, DNA damage response and tumorigenesis, by governing large amounts of key regulators for ubiquitination and proteasomal degradation (38). The results of previous studies have demonstrated that β-TrCP plays a vital role in carcinogenesis via promoting the degradation of its substrates, including oncoproteins and tumor suppressors (38). Specifically, the results of previous studies demonstrated that β-TrCP is upregulated in liver cancer tissues (39,40).…”

Section: Discussionmentioning

confidence: 99%

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Activation of the β‑TrCP/IκBα/inflammation axis limits the sensitivity of liver cancer cells to neddylation inhibition

et al. 2022

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Upregulation of protein neddylation occurs in numerous types of human cancer, including liver cancer. MLN4924, a potent neddylation-inhibiting pharmacological agent, demonstrates anticancer ability in numerous cancers. However, the sensitivity of MLN4924 in liver cancer remains unsatisfactory due to factors causing resistance. RT-qPCR and western blotting were utilized to assess the mRNA and protein levels of genes, respectively. Cell Counting Kit-8 assay and colony formation assays were employed to assess cell viability and proliferation. The pathway of protein degradation and stability were determined by western blotting after treatment with MG132 and cycloheximide. An immunoprecipitation assay was utilized to detect the ubiquitination of protein. An in vitro ubiquitination assay was used to determine the ubiquitin linkage. To the best of our knowledge, the present study was the first to demonstrate that NF-κB inhibitor α (IκBα) downregulation and subsequent inflammation in response to MLN4924 limited the antitumor potential of MLN4924. Ectopic expression of IκBα enhanced the antitumor potential of MLN4924 in liver cancer cells. Moreover, the results of the present study demonstrated that MLN4924 decreased IκBα via promoting the K48 linkage of ubiquitin to IκBα. Mechanistic studies demonstrated that MLN4924 enhanced the protein stability of β-transducin repeat-containing protein (β-TrCP), promoting the ubiquitination of IκBα, which led to the ubiquitin-mediated degradation of IκBα. In addition, the results of the present study also demonstrated that β-TrCP knockdown markedly inhibited MLN4924 from suppressing the growth of liver cancer cells, via attenuating MLN4924-mediated IκBα downregulation and inflammation. Collectively, these results indicated that the β-TrCP/IκBα/inflammation pathway may act as a novel resistance factor of MLN4924, and targeting β-TrCP may be beneficial for the treatment of liver cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Activation of the β‑TrCP/IκBα/inflammation axis limits the sensitivity of liver cancer cells to neddylation inhibition

et al. 2022

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“…β-TrcP2, also known as FBXW11, has been characterized to take part in tumorigenesis ( 36 ). FBXW11 activated the β-catenin/TCF and NF-kappa B pathways and increased cell proliferation in lymphocytic leukemia ( 37 ).…”

Section: Lncrnas Regulate the Expression Of F-box Proteinsmentioning

confidence: 99%

The functions of long noncoding RNAs on regulation of F-box proteins in tumorigenesis and progression

et al. 2022

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Accumulated evidence has revealed that F-box protein, a subunit of SCF E3 ubiquitin ligase complexes, participates in carcinogenesis and tumor progression via targeting its substrates for ubiquitination and degradation. F-box proteins could be regulated by cellular signaling pathways and noncoding RNAs in tumorigenesis. Long noncoding RNA (lncRNA), one type of noncoding RNAs, has been identified to modulate the expression of F-box proteins and contribute to oncogenesis. In this review, we summarize the role and mechanisms of multiple lncRNAs in regulating F-box proteins in tumorigenesis, including lncRNAs SLC7A11-AS1, MT1JP, TUG1, FER1L4, TTN-AS1, CASC2, MALAT1, TINCR, PCGEM1, linc01436, linc00494, GATA6-AS1, and ODIR1. Moreover, we discuss that targeting these lncRNAs could be helpful for treating cancer via modulating F-box protein expression. We hope our review can stimulate the research on exploration of molecular insight into how F-box proteins are governed in carcinogenesis. Therefore, modulation of lncRNAs is a potential therapeutic strategy for cancer therapy via regulation of F-box proteins.

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“…In addition, the inhibition of β-TrCP can enhance the antiproliferative effect of antitumor drugs on breast cancer cells, thus inhibiting NF-κB activity [ 218 ]. Although the β-TrCP E3 ligase plays a key role in regulating immune response [ 219 ], the mechanism of β-TrCP inhibitors in tumor immunity remains unclear. Therefore, future studies should analyze the regulation of targeted β-TrCP in tumor immunity.…”

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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The characteristics and roles of β‐TrCP1/2 in carcinogenesis

Cited by 46 publications

References 165 publications

Activation of the β‑TrCP/IκBα/inflammation axis limits the sensitivity of liver cancer cells to neddylation inhibition

Activation of the β‑TrCP/IκBα/inflammation axis limits the sensitivity of liver cancer cells to neddylation inhibition

The functions of long noncoding RNAs on regulation of F-box proteins in tumorigenesis and progression

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

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