The protein kinase OSR1 has been highlighted as a biomarker for a poor prognosis in breast cancer (BC) patients. To further decipher the mechanism underpinning this, we studied the expression, phosphorylation status, and catalytic activity of OSR1 across a series of BC cell lines. OSR1 was found to be expressed across the various luminal and triple negative BC (TNBC) cell lines studied, although it was only constitutively active in the highly migratory TNBC cell line MDA-MB-231. Although this cell line carries p53 mutations, our data indicated that OSR1 constitutive kinase activity of the OSR1 in MDA-MB-231 was independent of p53. Interestingly, the inhibition of OSR1 had no significant impact on MDA-MB-231 cell viability, but it was found to contribute to its substantial cell migration and invasion, as this was significantly attenuated by the WNK/OSR1 inhibitor WNK463. Analogously, the overexpression of constitutively active OSR1 in the poorly migrating BC cell line MCF7 enhanced its cell mobility. Collectively, our results indicate that the pharmacological inhibition of OSR1 could be a promising novel strategy for preventing the oncogenic potential of TNBC.

01 Nov 2024·American Journal of Physiology-Renal Physiology

Macrophage SPAK deletion limits a low potassium-induced kidney inflammatory program

Article

Author: Zhang, Yahua ; Wu, Aihua ; Terker, Andrew S. ; Delpire, Eric ; Harris, Raymond C. ; Bock, Fabian ; Arroyo, Juan Pablo ; Zhang, Ming-Zhi

Global Ste20p-related proline alanine-rich kinase (SPAK) deletion protects against harmful kidney effects of dietary K+ deficiency. Exposure to low K+ conditions increases SPAK phosphorylation and induces SPAK to adopt a punctate staining pattern. Macrophage-specific deletion of SPAK confers protection to low K+-induced kidney injury in vivo. Macrophage-expressed SPAK plays a key role in the development of kidney injury in response to a low K+ diet.

04 Sep 2024·Cancer Research

WNK1 Interaction with KEAP1 Promotes NRF2 Stabilization to Enhance the Oxidative Stress Response in Hepatocellular Carcinoma

Article

Author: Xiu, Mengxi ; Ma, Muyuan ; Yu, Shijun ; Xie, Dacheng ; Gao, Yong ; Chen, Jingde ; Li, Yandong ; Xie, Keping ; Fan, Kailing ; Li, Li

AbstractCellular oxidative stress plays a key role in the development and progression of hepatocellular carcinoma (HCC). A better understanding of the processes that regulate reactive oxygen species (ROS) homeostasis could uncover improved strategies for treating HCC. Herein, we identified protein kinase with-no-lysine kinase 1 (WNK1) as an antioxidative factor and therapeutic target in HCC. In human HCC, WNK1 expression was increased and correlated with poor patient prognosis. WNK1 knockdown significantly inhibited cell proliferation and xenograft tumor growth. Mechanistically, WNK1 competed with nuclear factor erythroid 2–related factor 2 (NRF2) for binding with the partial Kelch domain of Kelch-like ECH-associated protein 1 (KEAP1), reducing NRF2 ubiquitination and promoting NRF2 accumulation and nuclear translocation to increase antioxidant response. WNK1 silencing increased H2O2-induced apoptosis and inhibited cell growth by elevating ROS levels, which could be rescued by treatment with the antioxidant N-acetylcysteine and NRF2 activator tert-butylhydroquinone. Liver-specific WNK1 knockout mouse models of HCC substantiated that WNK1 promoted HCC development by regulating ROS levels. WNK463, an inhibitor of the WNK kinase family, suppressed HCC progression and altered the redox status. These findings suggest that WNK1 plays a critical role in HCC development and progression and that the WNK1-oxidative stress axis may be a promising therapeutic target for HCC.Significance: Inhibiting WNK1 induces NRF2 degradation and reduces the oxidative stress response to suppress hepatocellular carcinoma growth, indicating that targeting the WNK1–KEAP1–NRF2 axis is a potential strategy to treat liver cancer.

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Indication	Highest Phase	Country/Location	Organization	Date
Hepatocellular Carcinoma	Preclinical	China	Tongji University	17 Jun 2024
Hypertension	Preclinical	Switzerland	Novartis AG	05 Sep 2016

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