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.

Highlights

  • WNK kinases are a family of serine/threonine protein kinases with atypical kinase domain

  • We have found that zebrafish has two wnk1 genes, wnk1a and 1b, and each is required in embryonic angiogenesis during development [16]

  • Given that With-no-lysine (K)-1 (WNK1) plays a role in embryonic angiogenesis and may have multiple tumor-promoting effects, in this study we investigate the role of WNK1 in tumor-induced angiogenesis and the overall effect of WNK1 inhibition on tumor growth and metastasis

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Summary

Introduction

WNK (with-no-lysine [K]) kinases are a family of serine/threonine protein kinases with atypical kinase domain. Cancers 2020, 12, 575 featured by hypertension, hyperkalemia and hyperchloremic metabolic acidosis [2,3] These findings lead to the understanding of the role of WNK kinases in regulating epithelial ion transport through downstream ste20-related proline/alanine-rich kinase (SPAK) and related oxidative-stress response kinase-1 (OSR1) as well as some kinase-independent actions of WNKs [4,5,6,7,8,9,10]. We have found that zebrafish has two wnk genes, wnk1a and 1b, and each is required in embryonic angiogenesis during development [16]. The function of wnk in embryonic angiogenesis in zebrafish is downstream of vascular endothelial growth factor (VEGF) signaling [16]

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