ALCAP2 inhibits lung adenocarcinoma cell proliferation, migration and invasion via the ubiquitination of β-catenin by upregulating the E3 ligase NEDD4L

Zhang, Weijie; Zhang, Ruochen; Zeng, Yuanyuan; Li, Yue; Chen, Yikun; Zhou, Jieqi; Zhang, Yang; Wang, Anqi; Zhu, Jianjie; Liu, Zeyi; Yan, Zhaowei; Huang, Jianan

doi:10.1038/s41419-021-04043-6

Cited by 18 publications

(13 citation statements)

References 46 publications

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“…In prostate cancer cells, NEDD4L overexpression reduced its proliferation 31 . In addition, NEDD4L participated in JP1 (18‐F‐NFP‐JP1)‐inhibited melanoma growth and metastasis and prolonged the survival of mouse 32 and ALCAP2 (β, β‐dimethyl‐acryl‐alkannin)‐suppressed lung adenocarcinoma cell proliferation, migration and invasion 33 . NEDD4L inhibits bladder cancer progression by inactivating the p62/Keap1/Nrf2 pathway 34 .…”

Section: Discussionmentioning

confidence: 99%

NEDD4L is a promoter for angiogenesis and cell proliferation in human umbilical vein endothelial cells

Liu,

Song,

Zhou

et al. 2024

J Cellular Molecular Medi

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Dysregulated angiogenesis leads to neovascularization, which can promote or exacerbate various diseases. Previous studies have proved that NEDD4L plays an important role in hypertension and atherosclerosis. Hence, we hypothesized that NEDD4L may be a critical regulator of endothelial cell (EC) function. This study aimed to define the role of NEDD4L in regulating EC angiogenesis and elucidate their underlying mechanisms. Loss‐ and gain‐of‐function of NEDD4L detected the angiogenesis and mobility role in human umbilical vein endothelial cells (HUVECs) using Matrigel tube formation assay, cell proliferation and migration. Pharmacological pathway inhibitors and western blot were used to determine the underlying mechanism of NEDD4L‐regulated endothelial functions. Knockdown of NEDD4L suppressed tube formation, cell proliferation and cell migration in HUVECs, whereas NEDD4L overexpression promoted these functions. Moreover, NEDD4L‐regulated angiogenesis and cell progression are associated with the phosphorylation of Akt, Erk1/2 and eNOS and the expression of VEGFR2 and cyclin D1 and D3. Mechanically, further evidence was confirmed by using Akt blocker MK‐2206, Erk1/2 blocker U0126 and eNOS blocker L‐NAME. Overexpression NEDD4L‐promoted angiogenesis, cell migration and cell proliferation were restrained by these inhibitors. In addition, overexpression NEDD4L‐promoted cell cycle‐related proteins cyclin D1 and D3 were also suppressed by Akt blocker MK‐2206, Erk1/2 blocker U0126 and eNOS blocker L‐NAME. Our results demonstrated a novel finding that NEDD4L promotes angiogenesis and cell progression by regulating the Akt/Erk/eNOS pathways.

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Section: Discussionmentioning

confidence: 99%

NEDD4L is a promoter for angiogenesis and cell proliferation in human umbilical vein endothelial cells

Liu,

Song,

Zhou

et al. 2024

J Cellular Molecular Medi

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“…NEDD4 also promotes the resistance of NSCLC cells to erlotinib, and promotes tumor progression by negatively regulating PTEN [36]. On the other hand, during the progression of lung cancer, NEDD4 interacts with and promotes the ubiquitination and degradation of multiple oncogenes, such as MEKK5 and β-catenin [34,37]. Binding of HMGCL to NEDD4 might weaken the interaction between NEDD4 and these oncogenes, thus stabilizing these oncogenes and promoting the progression of lung cancer.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation by IKKβ Promotes the Degradation of HMGCL via NEDD4 in Lung Cancer

Zhong¹,

Xiong²,

Yang³

et al. 2023

Int. J. Biol. Sci.

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Inflammation and metabolic reprogramming are hallmarks of cancer. How inflammation regulates cancer metabolism remains poorly understood. In this study, we found that 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL), the enzyme that catalyzes the catabolism of leucine and promotes the synthesis of ketone bodies, was downregulated in lung cancer. Downregulation of HMGCL was associated with a larger tumor size and a shorter overall survival time. In a functional study, overexpression of HMGCL increased the content of β-hydroxybutyrate (β-HB) and inhibited the tumorigenicity of lung cancer cells, and deletion of HMGCL promoted de novo tumorigenesis in KP (Kras G12D ;P53 f/f ) mice. Mechanistically, tumor necrosis factor α (TNFα) treatment decreased the HMGCL protein level, and IKKβ interacted with HMGCL and phosphorylated it at Ser258, which destabilized HMGCL. Moreover, NEDD4 was identified as the E3 ligase for HMGCL and promoted its degradation. In addition, mutation of Ser258 to alanine inhibited the ubiquitination of HMGCL by NEDD4 and thus inhibited the anchorage-independent growth of lung cancer cells more efficiently than did wild-type HMGCL. In summary, this study demonstrated a link between TNFα-mediated inflammation and cancer metabolism.

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“…Aberrancy in cell cycle progression is an essential mechanism underpinning tumorigenesis ( 31 , 32 ). It is reported that CDCA4 can be transferred to the centrosome during mitosis and then to the intermediate region.…”

Section: Discussionmentioning

confidence: 99%

CDCA4 as a novel molecular biomarker of poor prognosis in patients with lung adenocarcinoma

et al. 2022

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Background: Because of the high incidence and poor prognoses of lung adenocarcinoma (LUAD), it is essential to identify cost-effective treatment options and accurate and reliable prognostic biomarkers. CDCA4 upregulation has been identified in many cancers. However, the prognostic importance of CDCA4 and its role in LUAD remain unknown.Methods: CDCA4 expression was assessed through IHC, Western blotting (WB) and RT-PCR. The Cancer Genome Atlas (TCGA) provided data from 513 patients to study the expression and prognostic relevance of CDCA4 in LUAD. This study used gene set enrichment analyses (GSEA), gene ontology and KEGG pathway analyses for elucidating potential mechanisms underpinning the function of CDCA4 in LUAD. We also investigated correlations between immune infiltration and CDCA4 expression with single specimen GSEA (ssGSEA).Results: According to database analysis and identification of patient tissue samples, CDCA4 expression in tumour tissues surpassed that in normal tissues (P< 0.001). Increased CDCA4 expression was positively correlated with a higher T, N, pathologic stage and poor primary therapy outcome. In addition, the Kaplan-Meier plotter exhibited that an elevated CDCA4 expression was related to worse disease-specific survival(DSS) and overall survival (OS) (DSS HR= 5.145, 95% CI=3.413-7.758, P<0.001; OS HR=3.570, 95% CI=2.472-5.155, P<0.001). Then multivariate COX regression analyses indicated that the CDCA4 gene was an independent risk consideration for prognoses. GO and KEGG results showed that CDCA4 and its neighbouring genes were enriched in the cell cycle and DNA replication. As determined by GSEA, CDCA4 was related to various immune-related signalling pathways (SPs), Homologous recombination, DNA replication and the cell cycle. SsGSEA analysis showed a significant association between CDCA4 expression and Th2 cells, mast cells, eosinophils and Th17 cells.

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ALCAP2 inhibits lung adenocarcinoma cell proliferation, migration and invasion via the ubiquitination of β-catenin by upregulating the E3 ligase NEDD4L

Cited by 18 publications

References 46 publications

NEDD4L is a promoter for angiogenesis and cell proliferation in human umbilical vein endothelial cells

NEDD4L is a promoter for angiogenesis and cell proliferation in human umbilical vein endothelial cells

Phosphorylation by IKKβ Promotes the Degradation of HMGCL via NEDD4 in Lung Cancer

CDCA4 as a novel molecular biomarker of poor prognosis in patients with lung adenocarcinoma

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