WNK1 kinase stimulates angiogenesis to promote tumor growth and metastasis

Zong Lin Sie, Ruei Yang Li, Bonifasius Putera Sampurna, Po Jui Hsu, Shu Chen Liu, Horng Dar Wang, Chou Long Huang, Chiou Hwa Yuh

Research output: Contribution to journalArticle

2 Scopus citations

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. 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.

Original languageEnglish (US)
Article number575
JournalCancers
Volume12
Issue number3
DOIs
StatePublished - Mar 2020

Keywords

  • Colorectal cancer
  • Hepatocellular carcinoma
  • Tumor-induced angiogenesis
  • With-no-lysine (K) kinase I
  • Zebrafish

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Sie, Z. L., Li, R. Y., Sampurna, B. P., Hsu, P. J., Liu, S. C., Wang, H. D., Huang, C. L., & Yuh, C. H. (2020). WNK1 kinase stimulates angiogenesis to promote tumor growth and metastasis. Cancers, 12(3), [575]. https://doi.org/10.3390/cancers12030575