NUAK family kinase 2 is a novel therapeutic target for prostate cancer

Abstract

Current advancements in prostate cancer (PC) therapies have been successful in slowing PC progression and increasing life expectancy; however, there is still no curative treatment for advanced metastatic castration resistant PC (mCRPC). Most treatment options target the androgen receptor, to which many PCs eventually develop resistance. Thus, there is a dire need to identify and validate new molecular targets for treating PC. We found NUAK family kinase 2 (NUAK2) expression is elevated in PC and mCRPC versus normal tissue, and expression correlates with an increased risk of metastasis. Given this observation and because NUAK2, as a kinase, is actionable, we evaluated the potential of NUAK2 as a molecular target for PC.NUAK2 is a stress response kinase that also plays a role in activation of the YAP cotranscriptional oncogene. Combining pharmacological and genetic methods for modulating NUAK2, we found that targeting NUAK2 in vitro leads to reduction in proliferation, three-dimensional tumor spheroid growth, and matrigel invasion of PC cells. Differential gene expression analysis of PC cells treated NUAK2 small molecule inhibitor HTH-02-006 demonstrated that NUAK2 inhibition results in downregulation of E2F, EMT, and MYC hallmark gene sets after NUAK2 inhibition. In a syngeneic allograft model and in radical prostatectomy patient derived explants, NUAK2 inhibition slowed tumor growth and proliferation rates. Mechanistically, HTH-02-006 treatment led to inactivation of YAP and the downregulation of NUAK2 and MYC protein levels. Our results suggest that NUAK2 represents a novel actionable molecular target for PC that warrants further exploration.

The NF-κB/NUAK2 signaling axis regulates pancreatic cancer progression by targeting SMAD2/3

“… 24 While recent studies have shown that NUAK2’s critical roles in liver and prostate cancers, its specific function in pancreatic cancer has remained unclear. 38 , 39 To address this gap, we initiated an investigation into the functional role of NUAK2 in pancreatic cancer cells by employing siRNA to target NUAK2. Our findings showed that NUAK2 knockdown inhibited the proliferation of pancreatic cancer cells, reduced their ability to migrate and invade, and induced apoptosis.…”

Activated Akt expression is associated with the recurrence of primary melanomas and further refines the prognostic and predictive values for relapse in acral melanomas

“…AMP‐related kinases have functions as sensors coupling cellular energy status to cell growth and proliferation. The activation of NUAK2 is speculated to result in cancer development and tumor progression (Fu et al, 2022; Gill et al, 2018; Namiki, Coelho, & Hearing, 2011; Yuan et al, 2018). NUAK2 has functions to phosphorate MYPT1 and to regulate the cytoskeleton, which results in facilitating cell proliferation by fiber maintenance, in addition to having a critical role in YAP‐driven tumorigenesis by regulating both the YAP and Hippo pathways (Gill et al, 2018) and NUAK2 also activates mTOR.…”

Extract2Chip—Bypassing Protein Purification in Drug Discovery Using Surface Plasmon Resonance

“…It belongs to the AMPK protein kinase family, acting as a critical sensor coupling cellular energy status to cell growth and proliferation [38]. The deregulation of NUAK2 has profound effects on cancer development and tumor progression, and is seen as a potential therapeutic target for several cancer-related diseases [39,40]. The NUAK2 amino acidic sequence (1-628) is predicted to bear two main disordered regions (355-493; 531-562), with the kinase domain comprising residues 53-303.…”