Non-canonical role of Hippo tumor suppressor serine/threonine kinase 3 STK3 in prostate cancer

Schirmer, Amelia; Driver, Lucy M.; Zhao, Megan T.; Wells, Carrow; Pickett, Julie E.; O'Bryne, Sean N; Eduful, Benjamin J.; Yang, Xuan; Howard, Lauren; You, Sungyong; Devi, Gayathri R.; DiGiovanni, John; Freedland, Stephen J.; Chi, Jen-Tsan; Drewry, David H.; Macías, Everardo

doi:10.1016/j.ymthe.2021.08.029

Cited by 22 publications

(20 citation statements)

References 29 publications

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“…Moya et al [ 14 ] found that the activity of yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in tumors was linked to the progression of liver tumors. The abnormal activation of the Hippo pathway upregulated androgen receptor (AR) activity in metastatic prostate cancer and reduced the overall survival (OS) of patients [ 15 ]. Through enrichment analysis, we identified that TOP2A regulated the cell cycle and DNA replication through the Hippo signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

DNA Topoisomerase II-α Regulated by miR-22-5p Promotes Hepatocellular Carcinoma Invasion and Migration through the Hippo Pathway

Zhao

Chen

Song

et al. 2022

Oxidative Medicine and Cellular Longevity

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DNA topoisomerases (TOPs) are dysregulated in various types of cancer. However, how TOP II-alpha (TOP2A) contributes to hepatocellular carcinoma (HCC) progression remains elusive. Cohort analysis revealed that the increased expression of TOP2A was associated with poor clinical outcomes and TOP2A was significantly upregulated in HCC tissues and cell lines. In vitro, TOP2A expression level is related to cell invasion and migration, which may be due to the alteration of epithelial-mesenchymal transition by the TOP2A. Moreover, we used verteporfin (a Hippo inhibitor) to test how the Hippo pathway promotes the effect of TOP2A on the HCC phenotype and found that TOP2A induces tumor progression through the Hippo pathway. Finally, miR-22-5p inhibited tumor progression by sponging TOP2A.

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Section: Introductionmentioning

confidence: 99%

DNA Topoisomerase II-α Regulated by miR-22-5p Promotes Hepatocellular Carcinoma Invasion and Migration through the Hippo Pathway

Zhao

Chen

Song

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…The pyrrolopyrazine derivative UNC-BE4-017 ( 4 ) was developed to target JAK kinases, but this inhibitor also has high in vitro activity against MST2. The compound was resynthesized and further characterized by Schirmer et al in 2022 . Increased kinome-wide selectivity was observed with a selectivity score S (10) of 0.03 when tested against 468 kinases at a concentration of 1 μM.…”

Section: Resultsmentioning

confidence: 99%

“…Increased kinome-wide selectivity was observed with a selectivity score S (10) of 0.03 when tested against 468 kinases at a concentration of 1 μM. Unfortunately, the in vitro on-target potency was not confirmed in cells where UNC-BE4-017 had only an EC 50 value of 7.6 μM (MST2) …”

Section: Resultsmentioning

confidence: 99%

Development of Selective Pyrido[2,3-d]pyrimidin-7(8H)-one-Based Mammalian STE20-Like (MST3/4) Kinase Inhibitors

Rak,

Menge,

Tesch

et al. 2024

J. Med. Chem.

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Mammalian STE20-like (MST) kinases 1−4 play key roles in regulating the Hippo and autophagy pathways, and their dysregulation has been implicated in cancer development. In contrast to the well-studied MST1/2, the roles of MST3/4 are less clear, in part due to the lack of potent and selective inhibitors. Here, we re-evaluated literature compounds, and used structure-guided design to optimize the p21-activated kinase (PAK) inhibitor G-5555 (8) to selectively target MST3/4. These efforts resulted in the development of MR24 (24) and MR30 ( 27) with good kinome-wide selectivity and high cellular potency. The distinct cellular functions of closely related MST kinases can now be elucidated with subfamily-selective chemical tool compounds using a combination of the MST1/2 inhibitor PF-06447475 (2) and the two MST3/4 inhibitors developed. We found that MST3/4-selective inhibition caused a cell-cycle arrest in the G1 phase, whereas MST1/2 inhibition resulted in accumulation of cells in the G2/M phase.

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“…To assess three-dimensional spheroid growth, cells were seeded at 500-5000 cells per well in a 96-well ultra-low attachment plate and allowed to form spheroids for 1-3 days as previously described. 16 Once clear spheroids were formed, treatments were added to the growth medium at indicated concentrations. All proliferation studies were monitored using the IncuCyte S3 live-cell imaging system (Sartorius Bioscience).…”

Section: Proliferation Assaysmentioning

confidence: 99%

“…To resolve YAP phospho-species phosbind acrylamide (PB-A) (APExBio; #F4002) was used to pour 6% acrylamide concentration and 50 µM PB-A concentration gel as previously described. 16 Gels were transferred onto nitrocellulose membranes and blocked with 5% milk or commercial OneBlock™ Western CL blocking buffer (Genessee Scientific) followed by overnight incubation with primary antibody NUAK2 (NBP1-81880;…”

Section: Western Blotsmentioning

confidence: 99%

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

Zhao

Driver

et al. 2021

Molecular Carcinogenesis

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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.

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Non-canonical role of Hippo tumor suppressor serine/threonine kinase 3 STK3 in prostate cancer

Cited by 22 publications

References 29 publications

DNA Topoisomerase II-α Regulated by miR-22-5p Promotes Hepatocellular Carcinoma Invasion and Migration through the Hippo Pathway

DNA Topoisomerase II-α Regulated by miR-22-5p Promotes Hepatocellular Carcinoma Invasion and Migration through the Hippo Pathway

Development of Selective Pyrido[2,3-d]pyrimidin-7(8H)-one-Based Mammalian STE20-Like (MST3/4) Kinase Inhibitors

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

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