Neddylation inhibition sensitises renal medullary carcinoma tumours to platinum chemotherapy

Shapiro, Daniel D.; Millward, Niki Zacharias; Tripathi, Durga Nand; Karki, Menuka; Bertocchio, Jean‐Philippe; Soeung, Melinda; He, Rong; Westerman, Mary E.; Gao, Jianjun; Rao, Priya; Lam, Truong; Jonasch, Eric; Perelli, Luigi; Cheng, Emily H.; Carugo, Alessandro; Heffernan, Timothy P.; Walker, Cheryl L.; Genovese, Giannicola; Tannir, Nizar M.; Karam, Jose A.; Msaouel, Pavlos

doi:10.1002/ctm2.1267

Cited by 5 publications

(4 citation statements)

References 43 publications

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“…Previous research has shown that NEDD8-activating enzyme (NAE) inhibitor, mln4924, enhances tumor sensitivity to oncolytic viro [ 39 ], platinum [ 40 ], and cisplatin [ 41 ] treatment through different mechanisms. Due to the lack of effective treatment for TNBC, PTX treatment resistance significantly affects patient prognosis.…”

Section: Discussionmentioning

confidence: 99%

Neddylation activated TRIM25 desensitizes triple-negative breast cancer to paclitaxel via TFEB-mediated autophagy

Zheng,

Qian,

Wang

et al. 2024

J Exp Clin Cancer Res

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Background Paclitaxel (PTX) treatment resistance is an important factor leading to poor prognosis in triple-negative breast cancer (TNBC), therefore there is an urgent need to identify new target for combination therapy. Neddylation is a post-translational process that introduces a ubiquitin-like protein called neural precursor cell expressed developmentally downregulated protein 8 (NEDD8). Previous studies have found that neddylation is activated in multiple tumors, but its relationship with PTX chemotherapy sensitivity has not been reported. Methods Differences in UBC12 and NEDD8 expression levels between PTX-sensitive and PTX-insensitive TNBC tissues were validated using public databases and immunohistochemistry. The in vitro and in vivo functional experiments were used to observe the effect of neddylation inhibition combined with PTX therapy on tumor progression. Co-IP, western blot and PCR assays were used to investigate the molecular mechanisms. Molecular docking was used to simulate the protein binding of UBC12 and TRIM25. Molecular dynamics simulation was used to observe the changes in TRIM25 protein conformation. Results We found that in TNBC that is insensitive to PTX, NEDD8 and NEDD8 conjugating enzyme UBC12 are highly expressed. Treatment with the NEDD8-activating enzyme (NAE) inhibitor mln4924 or knockdown of UBC12 significantly increased the sensitivity of the tumor to PTX, and this increase in sensitivity is related to UBC12-mediated autophagy activation. Mechanistically, UBC12 can transfer NEDD8 to E3 ubiquitin ligase tripartite motif containing 25 (TRIM25) at K117. Molecular dynamics simulations indicate that the neddylation modification of TRIM25 reduces steric hindrance in its RING domain, facilitating the binding of TRIM25 and ubiquitylated substrates. Subsequently, TRIM25 promotes the nuclear translocation of transcription factor EB (TFEB) and transcription of autophagy related genes by increasing K63-polyubiquitination of TFEB, thereby reducing tumor sensitivity to PTX. Conclusions Neddylation is activated in PTX-insensitive TNBC. Specifically, autophagy gene transcriptional activation mediated by the UBC12/TRIM25/TFEB axis reduces TNBC sensitivity to PTX. Neddylation suppression combination with PTX treatment shows a synergistic anti-tumor effect.

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Section: Discussionmentioning

confidence: 99%

Neddylation activated TRIM25 desensitizes triple-negative breast cancer to paclitaxel via TFEB-mediated autophagy

Zheng,

Qian,

Wang

et al. 2024

J Exp Clin Cancer Res

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“…For example, MLN4924 induces G2 cell cycle arrest and DNA damage in esophageal squamous cell carcinoma cells and sensitizes them to cisplatin [ 31 ]. Moreover, MLN4924 synergizes with carboplatin to inhibit renal medullary carcinoma cells by inhibiting DNA damage repair [ 32 ]. Likewise, treatment with MLN4924 was found to sensitize HNSCC cells to ionizing radiation (IR) and enhanced IR-induced xenografts inhibition in nude mice [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Neddylation inhibitor MLN4924 sensitizes head and neck squamous carcinoma cells to (S)-10-hydroxycamptothecin

Gu,

Lin,

et al. 2023

Eur J Med Res

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Head and neck squamous carcinoma (HNSCC) is the seventh most common cancer worldwide. Targeted therapeutic drugs for HNSCC are still being explored. Among them, (S)-10-hydroxycamptothecin (10-HCPT), a specific inhibitor of TOP1, functions by DNA double-strand breaks that can inhibit DNA replication and trigger apoptotic cell death subsequently. Previous studies have reported that MLN4924 exerts potent anti-tumor effects by inhibiting cullin–RING ligases and causing substrate accumulation in a variety of cancers. Here, we show that MLN4924 effectively causes dose-dependent accumulation of topoisomerase I (TOP1) and blocks TOP1 ubiquitination. Importantly, neddylation inhibition with MLN4924 acts synergistically with 10-HCPT to suppress cell growth, migration and apoptosis in HNSCC cells. Mechanistically, transcriptome sequencing shows that the cytotoxic effects of the combination of MLN4924 and 10-HCPT may involve activation of the NFKB1 pathway. Taken together, our results suggest that combined treatment with MLN4924 and 10-HCPT may be an effective strategy in HNSCC.

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“…Accordingly, p53 ∆31/∆31 cells exhibited a typical feature of cells from FA patients: the decreased capacity to repair DNA interstrand crosslinks induced by mitomycin C. Importantly, out of the 12 FA genes downregulated by p53 in mouse cells, 9 were also downregulated by p53 in human fibroblasts, and an increased expression of FA genes could be used as a marker of human tumor progression [26]. Furthermore, HCT116 cells (human colon carcinoma cells expressing a WT p53) were sensitized to mitomycin C upon p53 activation [26], and p53 activation improved platinum-based anti-cancer chemotherapy in a preclinical model [34]. Thus, again, our observations in mice appeared relevant to human disease processes.…”

Section: The Plot Thickens: Germline P53 Activation Underlies Feature...mentioning

confidence: 99%

p53 in the Molecular Circuitry of Bone Marrow Failure Syndromes

Rakotopare,

Toledo

2023

IJMS

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Mice with a constitutive increase in p53 activity exhibited features of dyskeratosis congenita (DC), a bone marrow failure syndrome (BMFS) caused by defective telomere maintenance. Further studies confirmed, in humans and mice, that germline mutations affecting TP53 or its regulator MDM4 may cause short telomeres and alter hematopoiesis, but also revealed features of Diamond–Blackfan anemia (DBA) or Fanconi anemia (FA), two BMFSs, respectively, caused by defects in ribosomal function or DNA repair. p53 downregulates several genes mutated in DC, either by binding to promoter sequences (DKC1) or indirectly via the DREAM repressor complex (RTEL1, DCLRE1B), and the p53-DREAM pathway represses 22 additional telomere-related genes. Interestingly, mutations in any DC-causal gene will cause telomere dysfunction and subsequent p53 activation to further promote the repression of p53-DREAM targets. Similarly, ribosomal dysfunction and DNA lesions cause p53 activation, and p53-DREAM targets include the DBA-causal gene TSR2, at least 9 FA-causal genes, and 38 other genes affecting ribosomes or the FA pathway. Furthermore, patients with BMFSs may exhibit brain abnormalities, and p53-DREAM represses 16 genes mutated in microcephaly or cerebellar hypoplasia. In sum, positive feedback loops and the repertoire of p53-DREAM targets likely contribute to partial phenotypic overlaps between BMFSs of distinct molecular origins.

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Neddylation inhibition sensitises renal medullary carcinoma tumours to platinum chemotherapy

Cited by 5 publications

References 43 publications

Neddylation activated TRIM25 desensitizes triple-negative breast cancer to paclitaxel via TFEB-mediated autophagy

Neddylation activated TRIM25 desensitizes triple-negative breast cancer to paclitaxel via TFEB-mediated autophagy

Neddylation inhibitor MLN4924 sensitizes head and neck squamous carcinoma cells to (S)-10-hydroxycamptothecin

p53 in the Molecular Circuitry of Bone Marrow Failure Syndromes

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