WNK1 promotes renal tumor progression by activating TRPC6‐NFAT pathway

Kim, Jihee; Hwang, Kyu Hee; Eom, Minseob; Kim, Min‐Seon; Park, Eun Young; Jeong, Yangsik; Park, Kyu Sang; Kuy, Seung

doi:10.1096/fj.201802019rr

Cited by 40 publications

(30 citation statements)

References 50 publications

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“…Indeed, the activity of various Ca 2+ channels is known to be important in the control of cancer cells growth and survival [4,25]. Specifically, TRPC6 channels are well established to be implicated in cell proliferation and migration [26] and various hypertrophic gene expression and reported to be mediated by NFAT pathway activation in normal [27] and cancer [28] cells. In this aspect, inhibition of TRPC6 expression or activity was suggested to be applied to target breast cancer cell proliferation and migration [26].…”

Section: Activation Of Trpc6 Channels In Mda-mb-231 Ppfurin-expressinmentioning

confidence: 99%

Furin Prodomain Ppfurin Enhances Soce Through trpc6 Activation in Breast Cancer Cells

López¹,

Siegfried²,

Cantonero³

et al. 2020

Preprint

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The intracellular calcium concentration ([Ca2+]i) modulation plays a key role in the regulation of cellular growth and survival in normal cells and failure of [Ca2+]i homeostasis is involved in tumor initiation and progression. Here we show that inhibition of Furin by its naturally occurring inhibitor the prodomain ppFurin in the MDA-MB-231 breast cancer cells resulted in enhanced SOCE through TRPC6 activation that associated reduced cells malignant phenotype. Expression of ppFurin in a stable manner in MDA-MB-231 and the melanoma MDA-MB-435 cell lines inhibits Furin activity as assessed by in vitro digestion assays. Accordingly, cell transfection experiments, revealed that the ppFurin-expressing cells are unable to process adequately the PC substrates proVEGF-C and proIGF-1R. Compared to MDA-MB-435 cells, expression of ppFurin in MDA-MB-231 significantly induces Ca2+ entry which is impaired by silencing of TRPC6 expression. Analysis of TRPC6 activation revealed its up-regulated tyrosine phosphorylation in ppFurin-expressing MDA-MB-231 cells. The expression of ppFurin in MDA-MB-231 cells reduced their viability and ability to migrate and enhanced their sensitization to the apoptosis inducer hydrogen peroxide. These findings suggest that Furin inhibition by ppFurin may be a useful strategy to interfere with Ca2+ mobilization leading to breast cancer cells malignant phenotype repression and reduction of their resistance to treatments.

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Section: Activation Of Trpc6 Channels In Mda-mb-231 Ppfurin-expressinmentioning

confidence: 99%

Furin Prodomain Ppfurin Enhances Soce Through trpc6 Activation in Breast Cancer Cells

López¹,

Siegfried²,

Cantonero³

et al. 2020

Preprint

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show abstract

“…In addition, Yu' group found extracellular vimentin modulates human dendritic cell activation, in order to prevent tissue-damage from contributing to the development of autoimmunity 23 . Similarly, Santos et al suggests that VIM may be a key regulator of the NLRP3 in ammasome 24 Additionally, WNK1 could promote renal tumor progression according to Kim's study 28 . Some researchers also deem it's related to immunity and in ammation 30 .…”

Section: Discussionmentioning

confidence: 97%

Bioinformatic gene analysis for potential biomarkers and therapeutic targets of kidney calculi-related renal cell carcinoma

Liu

et al. 2020

Preprint

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Kidney calculi (KC) is considered to be a potential cause of renal cell carcinoma（RCC）due to urinary retention, hydronephrosis, pyelonephritis, and carcinoma of renal pelvis. We searched co-expressed genes in order to explore the relationships between kidney calculi (KC) and renal cell carcinoma（RCC） and reveal potential biomarkers and therapeutic targets of kidney calculi-related renal cell carcinoma.KC-related differentially expressed genes (DEGs) were identified via bioinformatic analysis Gene Expression Omnibus (GEO) datasets GSE73680 and GSE117518. Simultaneously, RCC-related DEGs were also identified via bioinformatic analysis GEO datasets GSE14994 and GSE40435. Subsequently, co-DEGs of KC-related RCC were found, and extensive target prediction and network analyses methods were used to assess protein–protein interaction (PPI) networks, Gene Ontology (GO) terms and pathway enrichment for DEGs, and co-expressed DEGs coupled with corresponding predicted miRNAs involved in KC and RCC were assessed as well.We identified 832 DEGs in KC and RCC samples. The co-DEGs of VIM，DCN，WNK1 and PXDN coupled with corresponding predicted miRNAs, especially miR-181c-5p and miR-181d-5p may be significantly associated with KC-related RCC. The Co-DEGs of VIM，DCN，WNK1 and PXDN link KC and RCC. Finally, the top 5 miRNAs for each Co-DEGs may be potential signaling pathways for KC-relate RCC, especially miR-181c-5p and miR-181d-5p. Therefore, there is an association between KC and RCC and expression of VIM，DCN，WNK1 and PXDN genes may favor KC-related RCC.

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“…Literature suggests multiple potential mechanisms for WNK1-OSR1/SPAK signaling cascade to regulate endothelial cells for formation of blood vessels. Transmembrane Na + , K + , and Clion fluxes and calcium signaling affect migration of many cell types including endothelial cells [28,29]. WNK1 is a positive regulator of expression of transcription factors Slug, MMP2, ZEB1, which control endothelial cell migration [30].…”

Section: Discussionmentioning

confidence: 99%

WNK1 Kinase Stimulates Angiogenesis to Promote Tumor Growth and Metastasis

Sie

Sampurna

et al. 2020

Cancers

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With-no-lysine (K)-1 (WNK1) is the founding member of family of four protein kinases with atypical placement of catalytic lysine that play important roles in regulating epithelial ion transport. Gain-of-function mutations of WNK1 and WNK4 cause a mendelian hypertension and hyperkalemic disease. WNK1 is ubiquitously expressed and essential for embryonic angiogenesis in mice. Increasing evidence indicates the role of WNK kinases in tumorigenesis at least partly by stimulating tumor cell proliferation. Here, we show that human hepatoma cells xenotransplanted into zebrafish produced high levels of vascular endothelial growth factor (VEGF) and WNK1, and induced expression of zebrafish wnk1. Knockdown of wnk1 in zebrafish decreased tumor-induced ectopic vessel formation and inhibited tumor proliferation. Inhibition of WNK1 or its downstream kinases OSR1 (oxidative stress responsive kinase 1)/SPAK (Ste20-related proline alanine rich kinase) using chemical inhibitors decreased ectopic vessel formation as well as proliferation of xenotransplanted hepatoma cells. The effect of WNK and OSR1 inhibitors is greater than that achieved by inhibitor of VEGF signaling cascade. These inhibitors also effectively inhibited tumorigenesis in two separate transgenic zebrafish models of intestinal and hepatocellular carcinomas. Endothelial-specific overexpression of wnk1 enhanced tumorigenesis in transgenic carcinogenic fish, supporting endothelial cell-autonomous effect of WNK1 in tumor promotion. Thus, WNK1 can promote tumorigenesis by multiple effects that include stimulating tumor angiogenesis. Inhibition of WNK1 may be a potent anti-cancer therapy.

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WNK1 promotes renal tumor progression by activating TRPC6‐NFAT pathway

Cited by 40 publications

References 50 publications

Furin Prodomain Ppfurin Enhances Soce Through trpc6 Activation in Breast Cancer Cells

Furin Prodomain Ppfurin Enhances Soce Through trpc6 Activation in Breast Cancer Cells

Bioinformatic gene analysis for potential biomarkers and therapeutic targets of kidney calculi-related renal cell carcinoma

WNK1 Kinase Stimulates Angiogenesis to Promote Tumor Growth and Metastasis

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