標題: WNK1 Kinase Stimulates Angiogenesis to Promote Tumor Growth and Metastasis
作者: Sie, Zong-Lin
Li, Ruei-Yang
Sampurna, Bonifasius Putera
Hsu, Po-Jui
Liu, Shu-Chen
Wang, Horng-Dar
Huang, Chou-Long
Yuh, Chiou-Hwa
生物科技學系
Department of Biological Science and Technology
關鍵字: with-no-lysine (K) kinase I;tumor-induced angiogenesis;zebrafish;hepatocellular carcinoma;colorectal cancer
公開日期: 1-Mar-2020
摘要: 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.
URI: http://dx.doi.org/10.3390/cancers12030575
http://hdl.handle.net/11536/154597
DOI: 10.3390/cancers12030575
期刊: CANCERS
Volume: 12
Issue: 3
起始頁: 0
結束頁: 0
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