Discovery of a novel NUAK1 inhibitor against pancreatic cancer

Seo, Myeong-Seong; Jung, Kyung Hee; Kim, Kewon; Lee, Ji Eun; Han, Beom Seok; Ko, Soyeon; Kim, Jae Ho; Hong, Sungwoo; Lee, So Ha; Hong, Sung Kyung

doi:10.1016/j.biopha.2022.113241

Cited by 6 publications

(4 citation statements)

References 43 publications

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“…Treatment of PDAC cell lines with a highly selective NUAK1 inhibitor, HTH‐01‐015, was profoundly toxic, while NUAK1 depletion by RNAi significantly reduced proliferation of the same cell lines. These data concur with recent results from another lab using a distinct NUAK1 inhibitor [ 60 ] and with systems biology‐derived multi‐omic data showing a requirement for NUAK1 in PDAC [ 61 ]. Upregulation of NUAK1 moreover correlates with resistance of PDAC cells to Gemcitabine [ 62 ].…”

Section: Discussionsupporting

confidence: 91%

NUAK1 governs centrosome replication in pancreatic cancer via MYPT1/PP1β and GSK3β‐dependent regulation of PLK4

et al. 2023

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The AMP-activated protein kinase (AMPK)-related kinase NUAK1 (NUAK family SNF1-like kinase 1) has emerged as a potential vulnerability in MYC-dependent cancer but the biological roles of NUAK1 in different settings are poorly characterised, and the spectrum of cancer types that exhibit a requirement for NUAK1 is unknown. Unlike canonical oncogenes, NUAK1 is rarely mutated in cancer and appears to function as an obligate facilitator rather than a cancer driver per se. Although numerous groups have developed small-molecule NUAK inhibitors, the circumstances that would trigger their use and the unwanted toxicities that may arise as a consequence of on-target activity are thus undetermined. Reasoning that MYC is a key effector of RAS pathway signalling and the GTPase KRAS is almost uniformly mutated in pancreatic ductal adenocarcinoma (PDAC), we investigated whether this cancer type exhibits a functional requirement for NUAK1. Here, we show that high NUAK1 expression is associated with reduced overall survival in PDAC and that inhibition or depletion of NUAK1 suppresses growth of PDAC cells in culture. We identify a previously unknown role for NUAK1 in regulating accurate centrosome duplication and show that loss of NUAK1 triggers genomic instability. The latter activity is conserved in primary fibroblasts, raising the possibility of undesirable genotoxic effects of NUAK1 inhibition.

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Section: Discussionsupporting

confidence: 91%

NUAK1 governs centrosome replication in pancreatic cancer via MYPT1/PP1β and GSK3β‐dependent regulation of PLK4

et al. 2023

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“…Therefore, targeting NUAK1 may be a promising strategy for cancer treatment. Indeed, knockdown of NUAK1 or inhibition by small molecule inhibitors effectively suppressed tumor growth and metastasis in some mouse models (Seo et al, 2022; Wang et al, 2019). Despite the conspicuous role of NUAK1 in tumor progression, the mechanism of NUAK1 overexpression in hepatocellular carcinoma (HCC) is still being unraveled.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, targeting NUAK1 may be a promising strategy for cancer treatment. Indeed, knockdown of NUAK1 or inhibition by small molecule inhibitors effectively suppressed tumor growth and metastasis in some mouse models (Seo et al, 2022;Wang et al, 2019). gastric cancer and hepatocellular carcinoma, and this increase is positively correlated with the degree of malignancy of these cancers (Chu et al, 2021;Jaschke et al, 2020).…”

Section: The Expression Of Dkk1 and P-akt Is Positively Correlated Wi...mentioning

confidence: 99%

DKK1 promotes NUAK1 transcriptional expression through the activation Akt in hepatocellular carcinoma

Yao

Gao

Hou

et al. 2022

Cell Biology International

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NUAK1 is a serine/threonine kinase that has been shown to be associated with poor prognosis in several cancers. Although NUAK1 is frequently overexpressed at the transcript level in hepatocellular carcinoma (HCC), the actual role of NUAK1 and the mechanism of its overexpression in HCC has yet to be reported. In the present study, we found that NUAK1 expression was significantly increased in human HCC tumor tissues. Overexpression of NUAK1 dramatically enhanced HCC cells proliferation and migration in vitro. Stable induction of NUAK1 expression promoted tumor growth and tumor metastases to the lungs in the subcutaneous xenograft models and intravenous metastasis models. At the cellular level, enforced expression of Dickkopf‐1 (DKK1) activated the Akt signaling pathway, thereby promoting the mRNA and protein expression of NUAK1 in HCC cells. By contrast, depletion of DKK1 was found to attenuate the mRNA and protein expression of NUAK1. In the subcutaneous xenograft models, stable induction of DKK1 expression not only accelerated tumor growth but also increased p‐Akt and NUAK1 expression; whereas knockdown of DKK1 inhibited tumor growth, p‐Akt and NUAK1 expression. Furthermore, immunohistochemical analysis of 20 HCC clinical samples showed that the expression level of NUAK1 was positively correlated with DKK1 and p‐Akt. Taken together, we provide the first evidence that DKK1 promotes NUAK1 transcriptional expression via the activation Akt in HCC.

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“…On the other hand, cells were treated with 1 mg/mL DAPI for 10 min. Finally, cells were observed by a fluorescence microscope and three random fields were selected to count the number of positive-TUNEL cells (Seo et al, 2022).…”

Section: Tunel Assaymentioning

confidence: 99%

Anti‐NSCLC role of SCN4B by negative regulation of the cGMP‐PKG pathway: Integrated utilization of bioinformatics analysis and in vitro assay validation

Yang,

Liu,

2024

Drug Development Research

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Non‐small cell lung cancer (NSCLC) is a malignant tumor with low overall cure and survival rates. Uncovering abnormally expressed genes is significantly important for developing novel targeted therapies in NSCLC. This study aimed to discover new differentially expressed genes (DEGs) of NSCLC. The DEGs of NSCLC were identified in eight data sets from Gene Expression Omnibus (GEO) database. The expression profiles and the prognostic significance of SCN4B in LUAD and LUSC were analyzed using GEPIA database. LinkedOmics was used to identify co‐expressed genes with SCN4B, which were further subjected to KEGG pathway enrichment analysis. SCN4B‐overexpressing plasmid (pcDNA/SCN4B) was transfected into A549 and NCI‐H2170 cells to elevate the expression of SCN4B. MTT and TUNEL assays were performed to evaluate cell viability and apoptosis. Relying on the screened DEGs from GEO database, we identified that SCN4B was significantly downregulated in LUAD and LUSC. We confirmed the downregulation of SCN4B in NSCLC tissues using GEPIA database. SCN4B has a prognostic value in LUAD, but not LUSC. KEGG pathway enrichment analysis of SCN4B‐related genes showed that cGMP‐PKG signaling pathway might be involved in the role of SCN4B in NSCLC. Overexpression of SCN4B in A549 and NCI‐H2170 cells inhibited the cell viability. Besides, SCN4B overexpression induced apoptosis of A549 and NCI‐H2170 cells. SCN4B inhibited the expression of PKG1 and p‐CREB in NSCLC cells. Moreover, the inhibitory effects of SCN4B on tumor malignancy were attenuated by the activator of PKG. In conclusion, integrated bioinformatical analysis proved that SCN4B was downregulated and had a prognostic significance in NSCLC. In vitro experimental studies demonstrated that SCN4B regulated NSCLC cells viability and apoptosis via inhibiting cGMP‐PKG signaling pathway.

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Discovery of a novel NUAK1 inhibitor against pancreatic cancer

Cited by 6 publications

References 43 publications

NUAK1 governs centrosome replication in pancreatic cancer via MYPT1/PP1β and GSK3β‐dependent regulation of PLK4

NUAK1 governs centrosome replication in pancreatic cancer via MYPT1/PP1β and GSK3β‐dependent regulation of PLK4

DKK1 promotes NUAK1 transcriptional expression through the activation Akt in hepatocellular carcinoma

Anti‐NSCLC role of SCN4B by negative regulation of the cGMP‐PKG pathway: Integrated utilization of bioinformatics analysis and in vitro assay validation

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