WNK1 in Malignant Behaviors: A Potential Target for Cancer?

Jung, Ji-Ung; Jaykumar, Ankita B.; Cobb, Melanie H.

doi:10.3389/fcell.2022.935318

Cited by 5 publications

(5 citation statements)

References 139 publications

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“…Furthermore, we observed a dose-dependent increase in SYVN1 expression and a corresponding decrease in MNK1/2 and p-eIF4E levels upon treatment with increasing concentrations of VNLG-152R ( Figures 3C, D ). As expected, we also observed a dose-dependent decrease in other downstream oncoproteins involved in breast cancer cell migration, invasion, and cell cycle progression such as WNK1 (kinase with no lysine (K) 1) ( 45 , 46 ), and Cyclin-D1 ( 47 , 48 ), respectively ( Figure 3D ).…”

Section: Resultssupporting

confidence: 83%

“…Another significant finding of this study is that VNLG-152R caused dose-dependent depletion of WNK1 ( Figure 3D ) which is implicated in cell migration, invasion, and metastasis in multiple cancer types including glioblastoma ( 83 ), prostate cancer ( 84 ), non-small cell lung cancer ( 85 ), and breast cancer ( 45 , 46 , 86 , 87 ). Because metastasis is the major cause of mortality in patients with breast cancer ( 88 ), we posit that our compounds can be developed as small molecules therapeutics with the characteristics of inhibiting both cell proliferation and metastasis, which would undoubtedly have a major impact on mortality in patients with breast cancer.…”

Section: Discussionmentioning

confidence: 62%

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VNLG-152R and its deuterated analogs potently inhibit/repress triple/quadruple negative breast cancer of diverse racial origins in vitro and in vivo by upregulating E3 Ligase Synoviolin 1 (SYVN1) and inducing proteasomal degradation of MNK1/2

Thankan,

Thomas,

Purushottamachar

et al. 2023

Front. Oncol.

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Triple-negative breast cancer (TNBC) and its recently identified subtype, quadruple negative breast cancer (QNBC), collectively account for approximately 13% of reported breast cancer cases in the United States. These aggressive forms of breast cancer are associated with poor prognoses, limited treatment options, and lower overall survival rates. In previous studies, our research demonstrated that VNLG-152R exhibits inhibitory effects on TNBC cells both in vitro and in vivo and the deuterated analogs were more potent inhibitors of TNBC cells in vitro. Building upon these findings, our current study delves into the molecular mechanisms underlying this inhibitory action. Through transcriptome and proteome analyses, we discovered that VNLG-152R upregulates the expression of E3 ligase Synoviolin 1 (SYVN1), also called 3-hydroxy-3-methylglutaryl reductase degradation (HRD1) in TNBC cells. Moreover, we provide genetic and pharmacological evidence to demonstrate that SYVN1 mediates the ubiquitination and subsequent proteasomal degradation of MNK1/2, the only known kinases responsible for phosphorylating eIF4E. Phosphorylation of eIF4E being a rate-limiting step in the formation of the eIF4F translation initiation complex, the degradation of MNK1/2 by VNLG-152R and its analogs impedes dysregulated translation in TNBC cells, resulting in the inhibition of tumor growth. Importantly, our findings were validated in vivo using TNBC xenograft models derived from MDA-MB-231, MDA-MB-468, and MDA-MB-453 cell lines, representing different racial origins and genetic backgrounds. These xenograft models, which encompass TNBCs with varying androgen receptor (AR) expression levels, were effectively inhibited by oral administration of VNLG-152R and its deuterated analogs in NRG mice. Importantly, in direct comparison, our compounds are more effective than enzalutamide and docetaxel in achieving tumor growth inhibition/repression in the AR+ MDA-MD-453 xenograft model in mice. Collectively, our study sheds light on the involvement of SYVN1 E3 ligase in the VNLG-152R-induced degradation of MNK1/2 and the therapeutic potential of VNLG-152R and its more potent deuterated analogs as promising agents for the treatment of TNBC across diverse patient populations.

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Section: Resultssupporting

confidence: 83%

Section: Discussionmentioning

confidence: 62%

VNLG-152R and its deuterated analogs potently inhibit/repress triple/quadruple negative breast cancer of diverse racial origins in vitro and in vivo by upregulating E3 Ligase Synoviolin 1 (SYVN1) and inducing proteasomal degradation of MNK1/2

Thankan,

Thomas,

Purushottamachar

et al. 2023

Front. Oncol.

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“…Importantly, recent studies revealed that TRIM27 is elevated in human cancers ( 59 ) and is required for TNBC tumor growth in mouse xenograft models ( 60 ). WNK1 also has been linked to multiple cancers ( 61 ). Our previous work demonstrated that WNK1 regulates endothelial cell migration and angiogenesis by regulating downstream signaling proteins ( 62 ).…”

Section: Discussionmentioning

confidence: 99%

WNK1 controls endosomal trafficking through TRIM27-dependent regulation of actin assembly

Jung

Cobb

2023

Proc. Natl. Acad. Sci. U.S.A.

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The protein kinase WNK1 (with-no-lysine 1) influences trafficking of ion and small-molecule transporters and other membrane proteins as well as actin polymerization state. We investigated the possibility that actions of WNK1 on both processes are related. Strikingly, we identified the E3 ligase tripartite motif-containing 27 (TRIM27) as a binding partner for WNK1. TRIM27 is involved in fine tuning the WASH (Wiskott–Aldrich syndrome protein and SCAR homologue) regulatory complex which regulates endosomal actin polymerization. Knockdown of WNK1 reduced the formation of the complex between TRIM27 and its deubiquitinating enzyme USP7 (ubiquitin-specific protease 7), resulting in significantly diminished TRIM27 protein. Loss of WNK1 disrupted WASH ubiquitination and endosomal actin polymerization, which are necessary for endosomal trafficking. Sustained receptor tyrosine kinase (RTK) expression has long been recognized as a key oncogenic signal for the development and growth of human malignancies. Depletion of either WNK1 or TRIM27 significantly increased degradation of the epidermal growth factor receptor (EGFR) following ligand stimulation in breast and lung cancer cells. Like the EGFR, the RTK AXL was also affected similarly by WNK1 depletion but not by inhibition of WNK1 kinase activity. This study uncovers a mechanistic connection between WNK1 and the TRIM27-USP7 axis and extends our fundamental knowledge about the endocytic pathway regulating cell surface receptors.

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“…It is also reported that WNT1 tend to interact with hydrophobic domains of partner proteins "defending" them from abnormal aggregation [127]. WNK1 activity is known to correlate with tumor malignancy [128], but there is currently no evidence that pathologic WNK1 aggregation is associated with the disease.…”

Section: In Depth Analysis Of Highly Disordered Proteins From Various...mentioning

confidence: 99%

Chaotic aging: Intrinsically disordered proteins in aging-related processes

Manyilov

Ilyinsky

Nesterov

et al. 2023

Preprint

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The development of aging is associated with the disruption of key cellular processes manifested as well-established hallmarks of aging. Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) have no stable tertiary structure that provide them a power to be configurable hubs in signaling cascades and regulate many processes, potentially including those related to aging. There is a need to clarify the roles of IDPs/IDRs in aging. The dataset of 1624 aging-related proteins was collected from established aging databases and experimental studies. There is a noticeable presence of IDPs/IDRs, accounting for about 36% of the aging-related dataset, which is comparable to the disorder content of the whole human proteome (about 40%). A Gene Ontology analysis of the our Aging proteome reveals an abundance of IDPs/IDRs in one-third of aging-associated processes, especially in genome regulation. Signaling pathways associated with aging also contain IDPs/IDRs on different hierarchical levels. Protein-protein interaction network analysis showed that IDPs present in different clusters associated with different aging hallmarks. Protein cluster with IDPs enrichment and high liquid-liquid phase separation (LLPS) probability has 'nuclear' localization and DNA-associated functions, related to aging hallmarks: genomic instability, telomere attrition, epigenetic alterations, stem cells exhaustion. Some IDPs related to aging with high LLPS propensity were identified as 'dangerous' based on the prediction of their propensity to aggregation. Overall, our analyses indicate that IDPs/IDRs play significant roles in aging-associated processes, particularly in the regulation of DNA functioning. IDP aggregation, which can lead to loss-of-function and toxicity, could be critically harmful to the cell. A structure-based analysis of aging and the identification of proteins that are particularly susceptible to disturbances can enhance our understanding of the molecular mechanisms of aging and open up new avenues for slowing it down.

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WNK1 in Malignant Behaviors: A Potential Target for Cancer?

Cited by 5 publications

References 139 publications

VNLG-152R and its deuterated analogs potently inhibit/repress triple/quadruple negative breast cancer of diverse racial origins in vitro and in vivo by upregulating E3 Ligase Synoviolin 1 (SYVN1) and inducing proteasomal degradation of MNK1/2

VNLG-152R and its deuterated analogs potently inhibit/repress triple/quadruple negative breast cancer of diverse racial origins in vitro and in vivo by upregulating E3 Ligase Synoviolin 1 (SYVN1) and inducing proteasomal degradation of MNK1/2

WNK1 controls endosomal trafficking through TRIM27-dependent regulation of actin assembly

Chaotic aging: Intrinsically disordered proteins in aging-related processes

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