Journal article
WNK1 Kinase Stimulates Angiogenesis to Promote Tumor Growth and Metastasis
Cancers, Vol.12(3), p.575
03/01/2020
DOI: 10.3390/cancers12030575
PMCID: PMC7139507
PMID: 32131390
Abstract
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. WNK1is 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.
Details
- Title: Subtitle
- WNK1 Kinase Stimulates Angiogenesis to Promote Tumor Growth and Metastasis
- Creators
- Zong-Lin Sie - National Health Research InstitutesRuei-Yang Li - National Health Research InstitutesBonifasius Putera Sampurna - National Health Research InstitutesPo-Jui Hsu - National Health Research InstitutesShu-Chen Liu - National Central UniversityHorng-Dar Wang - National Tsing Hua UniversityChou-Long Huang - Roy J. and Lucille A. Carver College of MedicineChiou-Hwa Yuh - National Health Research Institutes
- Resource Type
- Journal article
- Publication Details
- Cancers, Vol.12(3), p.575
- DOI
- 10.3390/cancers12030575
- PMID
- 32131390
- PMCID
- PMC7139507
- NLM abbreviation
- Cancers (Basel)
- ISSN
- 2072-6694
- eISSN
- 2072-6694
- Publisher
- Mdpi
- Number of pages
- 20
- Grant note
- DK111542 / National Institutes of Health, USA; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 105-2319-B-400-001 / MOST MOST 1082320-B-400 -005 -MY3 / Taiwan Ministry of Science and Technology
- Language
- English
- Date published
- 03/01/2020
- Academic Unit
- Nephrology; Internal Medicine
- Record Identifier
- 9984359836102771
Metrics
16 Record Views