New insights into the characteristics of DRAK2 and its role in apoptosis: From molecular mechanisms to clinically applied potential

Zheng, Yi; Li, Xinchao; Kuang, Lirun; Wang, Yong

doi:10.3389/fphar.2022.1014508

Cited by 6 publications

(4 citation statements)

References 149 publications

(180 reference statements)

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“…Drak2 responds to ROS in cells to regulate apoptosis. ROS can regulate Drak2 through PKD during T-cell activation [ 37 ]. Similarly, in our study, overexpression of SOD could resist ROS production to reduce the level of Drak2 .…”

Section: Discussionmentioning

confidence: 99%

Luteolin Protects Pancreatic β Cells against Apoptosis through Regulation of Autophagy and ROS Clearance

Han

Tao

et al. 2023

Pharmaceuticals

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Diabetes, which is mainly characterized by increased apoptosis and dysfunction of beta (β) cells, is a metabolic disease caused by impairment of pancreatic islet function. Previous studies have demonstrated that death-associated protein kinase-related apoptosis-inducing kinase-2 (Drak2) is involved in regulating β cell survival. Since natural products have multiple targets and often are multifunctional, making them promising compounds for the treatment of diabetes, we identified Drak2 inhibitors from a natural product library. Among the identified products, luteolin, a flavonoid, was found to be the most effective compound. In vitro, luteolin effectively alleviated palmitate (PA)-induced apoptosis of β cells and PA-induced impairment of primary islet function. In vivo, luteolin showed a tendency to lower blood glucose levels. It also alleviated STZ-induced apoptosis of β cells and metabolic disruption in mice. This function of luteolin partially relied on Drak2 inhibition. Furthermore, luteolin was also found to effectively relieve oxidative stress and promote autophagy in β cells, possibly improving β cell function and slowing the progression of diabetes. In conclusion, our findings show the promising effect of Drak2 inhibitors in relieving diabetes and offer a potential therapeutic target for the protection of β cells. We also reveal some of the underlying mechanisms of luteolin’s cytoprotective function.

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Section: Discussionmentioning

confidence: 99%

Luteolin Protects Pancreatic β Cells against Apoptosis through Regulation of Autophagy and ROS Clearance

Han

Tao

et al. 2023

Pharmaceuticals

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“…Docking studies indicated that compound 35 positions well into the ATP pocket and exhibited similar bindings with hinge region residues in CDK9 and CDK2, with this 5-chloro analog unexpectedly forming two additional halogen bonds with Lys48 and Asp167 residues in CDK9, whereas, such a halogen bond was absent in CDK2, indicating that the selectivity exhibited by 35 towards CDK9 might be related to the formation of these halogen bonds. Yet, while compounds 33 and 34 showed a significant cytotoxic activity against five human Death-associated protein (DAP) kinases, including DRAK2 (apoptosis-inducing kinase 2), are well known to perform apoptosis-related tasks in cells [78]. A number of studies have shown that DRAK2 is engaged in regulating the activation of T lymphocytes as well as pancreatic β-cell apoptosis in type I diabetes [78].…”

Section: Classes Of Anticancer Oximesmentioning

confidence: 99%

“…Yet, while compounds 33 and 34 showed a significant cytotoxic activity against five human Death-associated protein (DAP) kinases, including DRAK2 (apoptosis-inducing kinase 2), are well known to perform apoptosis-related tasks in cells [78]. A number of studies have shown that DRAK2 is engaged in regulating the activation of T lymphocytes as well as pancreatic β-cell apoptosis in type I diabetes [78]. This kinase also plays an important role in the development of tumor-related diseases via diverse mechanisms, and has been shown to be involved in the exacerbation of alcoholic fatty liver disease (NAFLD) through SRSF6-associated RNA selective splicing, the regulation of chronic lymphocytic leukemia and acute myeloid leukemia, as well as the progression of colorectal cancer [78].…”

Section: Classes Of Anticancer Oximesmentioning

confidence: 99%

The Fundamental Role of Oxime and Oxime Ether Moieties in Improving the Physicochemical and Anticancer Properties of Structurally Diverse Scaffolds

Fotie,

Matherne,

Mather

et al. 2023

IJMS

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The present review explores the critical role of oxime and oxime ether moieties in enhancing the physicochemical and anticancer properties of structurally diverse molecular frameworks. Specific examples are carefully selected to illustrate the distinct contributions of these functional groups to general strategies for molecular design, modulation of biological activities, computational modeling, and structure–activity relationship studies. An extensive literature search was conducted across three databases, including PubMed, Google Scholar, and Scifinder, enabling us to create one of the most comprehensive overviews of how oximes and oxime ethers impact antitumor activities within a wide range of structural frameworks. This search focused on various combinations of keywords or their synonyms, related to the anticancer activity of oximes and oxime ethers, structure–activity relationships, mechanism of action, as well as molecular dynamics and docking studies. Each article was evaluated based on its scientific merit and the depth of the study, resulting in 268 cited references and more than 336 illustrative chemical structures carefully selected to support this analysis. As many previous reviews focus on one subclass of this extensive family of compounds, this report represents one of the rare and fully comprehensive assessments of the anticancer potential of this group of molecules across diverse molecular scaffolds.

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“…Death-associated protein kinase 2 (DAPK2) belongs to the family of death-associated protein kinases and acts as a calcium/calmodulin-dependent kinase ( 21 ). DAPK2 participates in apoptosis, autophagy, myeloid differentiation, and erythropoiesis ( 22 , 23 ). Extensive researches have been conducted concerning the association of DRAK2 with the development of type 1 diabetes and non-alcoholic fatty liver disease ( 24 , 25 ).…”

Section: Introductionmentioning

confidence: 99%

Development of an anoikis-related gene signature and prognostic model for predicting the tumor microenvironment and response to immunotherapy in colorectal cancer

Li,

Weng,

Yang

et al. 2024

Front. Immunol.

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The effect of anoikis-related genes (ARGs) on clinicopathological characteristics and tumor microenvironment remains unclear. We comprehensively analyzed anoikis-associated gene signatures of 1057 colorectal cancer (CRC) samples based on 18 ARGs. Anoikis-related molecular subtypes and gene features were identified through consensus clustering analysis. The biological functions and immune cell infiltration were assessed using the GSVA and ssGSEA algorithms. Prognostic risk score was constructed using multivariate Cox regression analysis. The immunological features of high-risk and low-risk groups were compared. Finally, DAPK2-overexpressing plasmid was transfected to measure its effect on tumor proliferation and metastasis in vitro and in vivo. We identified 18 prognostic ARGs. Three different subtypes of anoikis were identified and demonstrated to be linked to distinct biological processes and prognosis. Then, a risk score model was constructed and identified as an independent prognostic factor. Compared to the high-risk group, patients in the low-risk group exhibited longer survival, higher enrichment of checkpoint function, increased expression of CTLA4 and PD-L1, higher IPS scores, and a higher proportion of MSI-H. The results of RT-PCR indicated that the expression of DAPK2 mRNA was significantly downregulated in CRC tissues compared to normal tissues. Increased DAPK2 expression significantly suppressed cell proliferation, promoted apoptosis, and inhibited migration and invasion. The nude mice xenograft tumor model confirmed that high expression of DAPK2 inhibited tumor growth. Collectively, we discovered an innovative anoikis-related gene signature associated with prognosis and TME. Besides, our study indicated that DAPK2 can serve as a promising therapeutic target for inhibiting the growth and metastasis of CRC.

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New insights into the characteristics of DRAK2 and its role in apoptosis: From molecular mechanisms to clinically applied potential

Cited by 6 publications

References 149 publications

Luteolin Protects Pancreatic β Cells against Apoptosis through Regulation of Autophagy and ROS Clearance

Luteolin Protects Pancreatic β Cells against Apoptosis through Regulation of Autophagy and ROS Clearance

The Fundamental Role of Oxime and Oxime Ether Moieties in Improving the Physicochemical and Anticancer Properties of Structurally Diverse Scaffolds

Development of an anoikis-related gene signature and prognostic model for predicting the tumor microenvironment and response to immunotherapy in colorectal cancer

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