Gossypol inhibits cullin neddylation by targeting SAG-CUL5 and RBX1-CUL1 complexes

Yu, Qing; Hu, Zhiguo; Shen, Yanwen; Jiang, Yihan; Pan, Peichen; Hou, Tingjun; Pan, Zhen‐Qiang; Huang, Jing; Sun, Yi

doi:10.1016/j.neo.2020.02.003

Cited by 23 publications

(23 citation statements)

References 68 publications

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“…There is a question that how small molecule cisplatin or carboplatin disrupts the RBX1–UBE2F binding. A recent study showed that gossypol, a natural compound derived from cotton seed, blocks the neddylation of both CUL-5 and CUL-1 through direct binding to RBX1–CUL-1 or RBX2–CUL-5 complex, indicating that a small molecular likely disrupts protein-protein interaction 30 . In this study, platinum or its intermediates might be located at the protein-protein interface between UBE2F and RBX1 to disrupt the UBE2F–RBX1 binding, which in turn may facilitate the binding of UBE2F–RBX2.…”

Section: Discussionmentioning

confidence: 99%

Induction of NEDD8-conjugating enzyme E2 UBE2F by platinum protects lung cancer cells from apoptosis and confers to platinum-insensitivity

et al. 2020

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Platinum is a widely used first-line chemotherapy in treating non-small cell lung cancer of adenocarcinoma. Unfortunately, platinum resistance leads to relapse and therapeutic failure, enabling the development of platinum-sensitization strategies to be of great clinical significance. Here, we report that the upregulation of the NEDD8-conjugating enzyme UBE2F is an important way for lung cancer cells to escape platinum-induced cell apoptosis, which confers to insensitivity to platinum-based chemotherapy. Mechanistically, platinum treatment impairs the complex formation for proteasome-mediated UBE2F degradation, evidenced by the weaker association between UBE2F and Ring-box protein 1 (RBX1), an essential component of Cullin-Ring E3 ligases (CRLs), thus leading to the accumulation of UBE2F. The accumulated UBE2F promotes the neddylation levels and activity of Cullin5, in accord with the lower expression of pro-apoptotic protein NOXA, a well-known substrate of Cullin-Ring E3 ligase 5 (CRL5). Additionally, knockout of UBE2F significantly sensitizes lung cancer cells to platinum treatment by enhancing the protein levels of NOXA and subsequently promoting cell apoptosis. Our observations uncover a previously unknown regulatory mechanism of UBE2F stability upon platinum chemotherapy and suggest that UBE2F might be a novel therapy target for sensitizing lung cancer cells to platinum-based chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Induction of NEDD8-conjugating enzyme E2 UBE2F by platinum protects lung cancer cells from apoptosis and confers to platinum-insensitivity

et al. 2020

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“…Cand1 is a Cul1 associated protein whose binding is mutually exclusive with the F-box Protein-Skp1 subcomplex and is also blocked by attachment of the ubiquitin-like protein Nedd8 to lysine 720 of Cul [36,37]. Zhihui Che et al [38]…”

Section: Discussionmentioning

confidence: 99%

Screening and Authentication of Key Genes and Prognostic Value Analysis in Oligodendroglial Tumors

Bao

Peng

2020

Preprint

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Background: Emerging evidence indicates that various functional genes with altered expression are involved in the human tumor progression. This study is aimed at identifying novel key genes that may be used for oligodendroglial tumor diagnosis, prognosis, and targeted therapy. Methods: This study included three expression proﬁles (GSE15824, GSE29796 and GSE108474) obtained from the Gene Expression Omnibus (GEO). GEO2R was used to analyze the diﬀerentially expressed genes (DEGs) between normal samples and oligodendroglial tumor, including oligodendroglioma and anaplastic oligodendroglioma. The functional and pathway enrichment analysis was performed by the Database for Annotation, Visualization and Integrated Discovery. A protein-protein interaction (PPI) network of the identiﬁed DEGs was constructed using the Search Tool for the Retrieval of Interacting Gene, and hub genes were identiﬁed. ONCOMINE and The Cancer Genome Atlas (TCGA) databases were used to verify the expression of the hub genes in oligodendroglial tumor tissues and the hub genes on the overall survival of oligodendroglial tumor patients. Results: A total of 128 DEGs were identiﬁed from the three expression proﬁles. These DEGs were enriched with functional processes and pathways related to oligodendroglial tumor pathogenesis. From the PPI network, five hub genes were identiﬁed. The expression of the five hub genes was all upregulated in oligodendroglial tumor tissues compared with the control tissues. Kaplan-Meier survival curves indicated that high expression of cullin 3 (CUL3), cop9 signalosome subunit 8 (COPS8), cullin associated and neddylation dissociated 1 (CAND1), F-box protein 22 (FBXO22), and leucine rich repeat containing 41 (LRRC41) predicted poor overall survival in oligodendroglial tumor patients (all log-rank P < 0.01). Conclusions: These results revealed that the DEGs may serve as candidate key genes during oligodendroglial tumor pathogenesis. The five hub genes, including CUL3, COPS8, CAND1, FBXO22, and LRRC41, may serve as promising prognostic biomarkers in oligodendroglial tumor.

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“…The NOXA–MCL1 complex has been shown to be degraded through proteasomal turnover regulated by MARCH5 and MTCH2 and that stabilization of this complex hinders the pro-survival role of MCL1 despite its accumulation [ 42 ]. Alternatively, gossypol, a precursor of AT101, has been shown to inhibit neddylation of both SAG-CUL5 and RBX1-CUL1, resulting in accumulation of both NOXA and MCL1 in multiple cell lines [ 43 ]. Whether these pathways are dysfunctional upon incubation with AT101, or whether the proteasome is overtaxed and unable to degrade the marked complexes remains unknown.…”

Section: Discussionmentioning

confidence: 99%

AT101 [(-)-Gossypol] Selectively Inhibits MCL1 and Sensitizes Carcinoma to BH3 Mimetics by Inducing and Stabilizing NOXA

Mallick

Eastman

2020

Cancers

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Anti-apoptotic BCL2 proteins are important targets for cancer therapy as cancers depend on their activity for survival. Direct inhibitors of MCL1 have entered clinical trials, although their efficacy may be limited by toxicity. An alternative approach may be to induce the pro-apoptotic protein NOXA which selectively inhibits MCL1 in cells. Many compounds originally proposed as inhibitors of the BCL2 family were subsequently found to induce the pro-apoptotic protein NOXA through the unfolded protein response. In the present study, we compared various putative BH3 mimetics across a panel of carcinoma cell lines and measured expression of NOXA protein and mRNA, as well as the kinetics of NOXA induction. We found that AT101 [(-)-gossypol] induces high levels of NOXA in carcinoma cell lines yet cells survive. When combined with an appropriate BCL2 or BCL-XL inhibitor, NOXA-dependent sensitization occurs. NOXA protein continues to accumulate for many hours after AT101 is removed, providing a window for administering these combinations. As MCL1 promotes drug resistance and overall survival, we propose that NOXA induction is an alternative therapeutic strategy to target MCL1 and either kill cancer cells that are dependent on MCL1 or sensitize cancer cells to other BCL2 inhibitors.

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Gossypol inhibits cullin neddylation by targeting SAG-CUL5 and RBX1-CUL1 complexes

Cited by 23 publications

References 68 publications

Induction of NEDD8-conjugating enzyme E2 UBE2F by platinum protects lung cancer cells from apoptosis and confers to platinum-insensitivity

Induction of NEDD8-conjugating enzyme E2 UBE2F by platinum protects lung cancer cells from apoptosis and confers to platinum-insensitivity

Screening and Authentication of Key Genes and Prognostic Value Analysis in Oligodendroglial Tumors

AT101 [(-)-Gossypol] Selectively Inhibits MCL1 and Sensitizes Carcinoma to BH3 Mimetics by Inducing and Stabilizing NOXA

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