Serine/Threonine Kinase 17A Is a Novel Candidate for Therapeutic Targeting in Glioblastoma

Mao, Pingping; Hever-Jardine, Mary P.; Rahme, Gilbert J.; Yang, Eric C.; Tam, Janice; Kodali, Anita; Biswal, Bijesh K.; Fadul, Camilo E.; Gaur, Arti; Israel, Mark A.; Spinella, Michael J.

doi:10.1371/journal.pone.0081803

Cited by 26 publications

(38 citation statements)

References 34 publications

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“…The authors also found elevated expression of EGFR, STK17A, MRLC, and anillin in human tumor tissue and a correlation of the expression of these proteins. While STK17A was not mutated, its expression was upregulated, and patients with a higher level experienced a poor prognosis, as reported previously (8).…”

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confidence: 83%

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Drak, Drak, Goose: A New Signaling Axis in Glioblastoma

Lathia

2019

Cancer Research

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While many molecular alterations in glioblastoma (GBM), the most common primary malignant brain tumor, have been defined, the intricate signaling networks associated with these alterations that represent actionable therapeutic targets are less well established. Chen and colleagues leverage a Drosophila GBM model to identify a conserved signaling axis downstream of the EGFR and PI3K that involves the death-associated protein kinase (Drak), a cytoplasmic serine/threonine kinase orthologous to the human kinase STK17A. Functional studies revealed that targeting this signaling axis attenuated mitosis and cytokinesis, providing a new pathway for therapeutic development in GBM. See related article by Chen et al., p. 1085

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supporting

confidence: 83%

“…Using the data generated in the Drosophila model, the authors turned to human GBM models and confirmed the role of STK17A, the human ortholog of Drak and a p53 target gene induced by DNA damage (8). STK17A knockdown resulted in decreased proliferation, increased apoptosis, and altered cell shape and adhesion.…”

mentioning

confidence: 86%

Drak, Drak, Goose: A New Signaling Axis in Glioblastoma

Lathia

2019

Cancer Research

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“…21 In contrast, DRAK1 overexpression in glioblastoma, where this gene is associated with tumor grade and survival in patients, promoted cell proliferation and resistance to genotoxic stress. 22 In this study, we demonstrated that DRAK1 is overexpressed in HNSCC cells and contributes to the resistance to TGF-β1 tumor-suppressive effects.…”

Section: Discussionmentioning

confidence: 60%

“…19 Moreover, DRAK1 is a direct target gene of p53 and enhances cisplatin-mediated toxicity by regulating reactive oxygen species (ROS) in testicular cancer cells. 21 However, Mao et al 22 recently demonstrated that DRAK1 was overexpressed in glioblastoma, where it was associated with tumor grade and patient survival, and promoted cell proliferation, migration, invasion and resistance to genotoxic agents.…”

Section: Introductionmentioning

confidence: 99%

Cytoplasmic DRAK1 overexpressed in head and neck cancers inhibits TGF-β1 tumor suppressor activity by binding to Smad3 to interrupt its complex formation with Smad4

et al. 2014

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Head and neck squamous cell carcinoma (HNSCC) is an extremely aggressive cancer with a poor prognosis and low patient survival. Because chemotherapy for advanced HNSCC is often ineffective, discovering new therapeutic targets that are important for HNSCC development and progression and elucidating their molecular mechanisms are required. In the present study, we describe the role of DRAK1 (death-associated protein kinase-related apoptosis-inducing kinase 1) as a novel negative regulator of the transforming growth factor-β (TGF-β) tumor suppressor signaling pathway for the first time in human HNSCC cells. DRAK1 was significantly overexpressed in primary human HNSCCs and in HNSCC cell lines. Through gain- and loss-of-function experiments, we demonstrated that the DRAK1 expression level regulated TGF-β1-induced transcriptional activity and expression of the tumor suppressor gene p21(Waf1/Cip1). DRAK1 depletion enhanced TGF-β1-induced growth inhibition in vitro and suppressed tumorigenicity in xenograft models in vivo. Mechanistically, DRAK1 was predominantly localized in the cytoplasm and bound to Smad3, thereby interrupting Smad3/Smad4 complex formation, which is the core process for the induction of tumor suppressor genes by TGF-β1. Thus, our findings suggest that cytoplasmic DRAK1 increases tumorigenic potential through inhibition of TGF-β1-mediated tumor suppressor activity in HNSCC cells and may be a potential therapeutic target for HNSCCs.

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“…Previously, this kinase has been associated with apoptosis due to its not otherwise specified function as a cell death-associated protein [20]. This gene has not been reported in ICC until now and may be a potential target gene for p53, induced by a variety of DNA-damaging agents, and therefore a possible target for anticancer therapy [21].…”

Section: Discussionmentioning

confidence: 99%

Use of Gene Expression Analysis for Discrimination of Primary and Secondary Adenocarcinoma of the Liver

et al. 2018

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Background: Due to late diagnosis and resistance to chemotherapy, most patients with cholangiocarcinoma have an unfavorable prognosis. Despite the use of immunohistochemistry (IHC) in clinical routine, differentiation between intrahepatic cholangiocarcinoma (ICC) and secondary adenocarcinomas of the liver is frequently not clear, leading to false diagnosis and treatment decisions. Methods: Oligonucleotide microarrays (Affymetrix Hu133A^©) were used for gene expression analysis of ICC (n = 11) and secondary adenocarcinomas (colorectal metastases; n = 6). By two-dimensional cluster analysis a specific gene expression profile of these tumors was established and confirmed by real-time polymerase chain reaction and IHC. Results: A total of 338 genes were significantly dysregulated (gene expression/fc ≥2; dysregulation in ≥60%) in both tumor groups. Using two-dimensional cluster analysis a fast, clear, and reproducible differentiation between ICC and colorectal metastases was possible in all cases. As potential biomarkers for differentiation, twelve genes (ICC: KRT7, DBN1, LCTB, LIF, STK17A, PIGF; metastases: TDGF1, HOXA9, TFF3, MYB, ABP1, BCL11A) were detected and will be used for further investigations. Conclusions: A specific gene expression profile for discrimination of primary and secondary adenocarcinoma of the liver could be established. In addition, marker genes for both cancers and their potential use as discrimination markers in clinical routine were also described partially for the first time.

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Serine/Threonine Kinase 17A Is a Novel Candidate for Therapeutic Targeting in Glioblastoma

Cited by 26 publications

References 34 publications

Drak, Drak, Goose: A New Signaling Axis in Glioblastoma

Drak, Drak, Goose: A New Signaling Axis in Glioblastoma

Cytoplasmic DRAK1 overexpressed in head and neck cancers inhibits TGF-β1 tumor suppressor activity by binding to Smad3 to interrupt its complex formation with Smad4

Use of Gene Expression Analysis for Discrimination of Primary and Secondary Adenocarcinoma of the Liver

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