A review on cullin neddylation and strategies to identify its inhibitors for cancer therapy

Bano, Iqra; Malhi, Moolchand; Zhao, Min; Giurgiulescu, Liviu; Sajjad, Hira; Kieliszek, Marek

doi:10.1007/s13205-022-03162-x

Cited by 6 publications

(3 citation statements)

References 114 publications

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“…Our research findings indicate that C-CBL mediated neddylation acts as an antagonist against insulin-associated cancer cell migration involving IRS1 and IRS2 in diverse cancer types. Amidst the growing interest in neddylation as a promising therapeutic target for cancer treatments, it is significant to emphasize that our research findings do not contradict the well-established anticancer effects of MLN4924, a known neddylation inhibitor [ 54 ]. As we advance in our understanding of the intricate interplay between insulin dysregulation and neddylation in cancer progression, careful evaluation of neddylation inhibitors in cancer patients with T2DM or hyperinsulinemia is necessary.…”

Section: Discussionmentioning

confidence: 88%

Neddylation of insulin receptor substrate acts as a bona fide regulator of insulin signaling and its implications for cancer cell migration

Park,

Moon,

Cho

et al. 2024

Cancer Gene Ther

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Irregularities in insulin signaling have significantly increased the risk of various cancers, yet the precise underlying mechanisms remain unclear. Within our study, we observed that inhibiting neddylation enhances cancer cell migration across different cancer types by activating both insulin receptor substrates 1 and 2 (IRS1 and IRS2), along with the PI3K/AKT signaling pathway. Notably, in the context of high-grade serous carcinoma (HGSC) patients, whether they had type 2 diabetes mellitus or not, IRS1 and IRS2 displayed a parallel relationship with each other while exhibiting an inverse relationship with NEDD8. We also identified C-CBL as an E3 ligase responsible for neddylating IRS1 and IRS2, with clinical evidence further confirming a reciprocal relationship between C-CBL and pAKT, thereby reinforcing the tumor suppressive role of C-CBL. Altogether, these findings suggest that neddylation genuinely participates in IRS1 and IRS2-dependent insulin signaling, effectively suppressing cancer cell migration. Thus, caution is advised when considering neddylation inhibitors as a treatment option for cancer patients, particularly those presenting with insulin signaling dysregulations linked to conditions like obesity-related type 2 diabetes or hyperinsulinemia.

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Section: Discussionmentioning

confidence: 88%

Neddylation of insulin receptor substrate acts as a bona fide regulator of insulin signaling and its implications for cancer cell migration

Park,

Moon,

Cho

et al. 2024

Cancer Gene Ther

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“…Compared with other ubiquitin-like molecules, Nedd8 has the structure closest to that of ubiquitin [9]. Although neddylation modi cation is similar to ubiquitination, the difference is that neddylation-modi ed proteins cannot be degraded by protein enzymes like ubiquitinated proteins and thus affect the abundance of substrates, but instead regulates the activity of proteins of substrates [29]. This implies that the mechanism of neddylation regulating embryonic development may be different from that of ubiquitin, which agrees with our experimental results.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of neddylation causes early developmental arrestment in mouse embryo because of the zygotic genome activation failure

Yang

Chen

et al. 2023

Preprint

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Background Maternal protein degradation in mammalian preimplantation embryos has yet to be fully understood. One major pathway is the ubiquitin-proteasome system. Recently, new forms of ubiquitination such as neddylation have been found to play important roles in a wide variety of biological processes, including reproduction. However, the molecular mechanism of neddylation in the early embryonic development of mammals is mostly unknown. Methods The zygotes were collected through in vitro fertilization and the expression of marker genes during embryonic development and zygotic genome activation (ZGA) was monitored after 24,48,72,96 hours of culture with MLN4924 (specific inhibition of neddylation) using real-time quantitative PCR. Single-cell RNA sequencing and quantitative PCR were applied to monitor and validate the changes in the downstream transcriptome. We utilized immunofluorescence and Western blotting to detect the expression and localization of proteins in mouse embryos. Results Blocking neddylation in mouse zygotes led to a statistically significant decrease in the cleavage rate to the 2-cell stage. Transcriptional profiling showed genes differentially expressed in pathways involving cell fate determination, cell differentiation, and cytoskeletal proteins. The expressions of zygotic ZGA markers were significantly reducejiand, indicating a significant downstream alteration in relevant pathways leading to the 2-cell stage arrest phenotype. A decrease in the level of RNA polymerase II in the nucleus was detected, showing impaired gene transcription in the embryo. We also identified a decrease in methyltransferase expression and concomitant reduction in histone H3K4 trimethylation, which may be the molecular mechanism of early embryonic developmental arrest caused by neddylation inhibition. Reduction of Yap1 was detected, suggesting aberrant downstream reactions of the Hippo signaling pathway. It also addressed the problem of the neddylation inhibition caused early embryonic arrest. Our study shed light upon new forms of ubiquitination regulating mammalian embryonic development and may contribute to further investigation of female infertility pathology. Conclusions Our data suggest that blocking neddylation leads to ZGA failure, possibly due to a decrease in H3K4me3 caused by a decrease in methyltransferase (KMT2D).

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“…In the 1960s, researchers considered the fundamental basis of bacterial gene transfer and used it to develop eukaryotic transfection technology [26]. The foundation of genetic engineering is the work of restriction enzymes and ligases, which were initially identified in the 1970s [27]. By using recombinant DNA technology, scientists can introduce targeted therapeutic genes into designed vectors [28].…”

Section: Introductionmentioning

confidence: 99%

An Overview of Emerging Trends in Gene Therapy for Cancer Treatment

Amin

2024

AJCEM

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Clinical trials have long recognized cancer treatment as a top priority. Different approaches have been devised for dealing with tumors of different types and at different stages. When it came to curing cancer, gene therapy was vital. The advancement of genome engineering technologies over the past thirty years has pushed forward gene therapy for the treatment and management of chronic diseases. It is the hope of researchers that one day they will be able to treat individuals with single gene disorders and complicated acquired diseases in a way that is both safe and successful. Gene delivery is a promising new method for detecting, diagnosing, and maybe treating cancer, made possible by recent developments in genetic engineering. Naked nucleic acid-based treatment, targeting microRNAs, oncolytic viral therapy, suicide gene-based therapy, targeting telomerase, cell-mediated gene therapeutics, and CRISPR/Cas9-based therapies are just few of the cancer medicines that have been created and tested in vitro and in vivo. This article provides a critical overview of the present and diverse cancer gene therapy methodologies, as well as a summary of the available viral and non-viral gene delivery mechanisms for gene therapy. In the future, biosafe carriers for gene products will play a crucial role in the prevention of cancer.

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A review on cullin neddylation and strategies to identify its inhibitors for cancer therapy

Cited by 6 publications

References 114 publications

Neddylation of insulin receptor substrate acts as a bona fide regulator of insulin signaling and its implications for cancer cell migration

Neddylation of insulin receptor substrate acts as a bona fide regulator of insulin signaling and its implications for cancer cell migration

Inhibition of neddylation causes early developmental arrestment in mouse embryo because of the zygotic genome activation failure

An Overview of Emerging Trends in Gene Therapy for Cancer Treatment

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