CDK15 promotes colorectal cancer progression via phosphorylating PAK4 and regulating β-catenin/ MEK-ERK signaling pathway

Huang, Chuntian; Du, Ruijuan; Jing, Xue; Liu, Kangdong; Qiao, Yan; Wu, Qiong; Yao, Ning; Yang, Lu; Zhou, Liting; Liu, Xuejiao; Xiang, Ping; Xin, Mingxia; Chen, Xiaojie; Kim, Dong Joon; Dong, Zigang; Li, Xiang

doi:10.1038/s41418-021-00828-6

Cited by 35 publications

(22 citation statements)

References 44 publications

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“…Other SC genes in the list with expected anti-tumor effect were upregulated, such as HPSE2 (heparanase 2) [ 77 ]. Similarly, genes implicated in tumorigenesis or progression were downregulated by the combinatory treatment, like SPRY1 (sprouty RTK signaling antagonist 1) [ 78 ], CDK15 (Cyclin-dependent kinase 15) [ 79 ], or VIM (vimentin) [ 80 ]. The checkpoint inhibitor CTLA4 (Cytotoxic T-Lymphocyte Antigen 4) was downregulated as well, which could potentiate the immune response in vivo when using the combination of UVI5008+Gem [ 81 ].…”

Section: Resultsmentioning

confidence: 99%

Synergistic Antitumoral Effect of Epigenetic Inhibitors and Gemcitabine in Pancreatic Cancer Cells

et al. 2022

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Epigenetic modifications could drive some of the molecular events implicated in proliferation, drug resistance and metastasis of pancreatic ductal adenocarcinoma (PDAC). Thus, epigenetic enzyme inhibitors could be the key to revert those events and transform PDAC into a drug-sensitive tumor. We performed a systematic study with five different epigenetic enzyme inhibitors (1, UVI5008, MS275, psammaplin A, and BIX01294) targeting either Histone Deacetylase (HDAC) 1 or 1/4, DNA methyltransferase 3a (DNMT3a), Euchromatic histone lysine methyltransferase 2 (EHMT2), or Sirtuin 1 (SIRT1), as well as one drug that restores the p53 function (P53R3), in three different human PDAC cell lines (SKPC-1, MIA PaCa-2, and BxPC-3) using 2D and 3D cell cultures. The synergistic effect of these antitumoral drugs with gemcitabine was tested and the most efficient combinations were characterized by RNA-seq. The inhibition of HDAC1/4 (MS275), HDAC1/4/SIRT1/DNMT3a (UVI5008) or EHMT2 (BIX01294) induced a significant reduction on the cell viability, even in gemcitabine-resistance cells. The combination of UVI5008 or MS275 with gemcitabine induced a synergistic effect at low concentration and the RNA-Seq analysis revealed some synergy candidate genes as potential biomarkers. Reverting aberrant epigenetic modifications in combination with gemcitabine offers an alternative treatment for PDAC patients, with an important reduction of the therapeutic dose.

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Section: Resultsmentioning

confidence: 99%

Synergistic Antitumoral Effect of Epigenetic Inhibitors and Gemcitabine in Pancreatic Cancer Cells

et al. 2022

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“…Recent findings have shown that the expression level of CDK15 elevated in CRC, and there was a negatively correlation between CDK15 and overall survival. Further studies of the mechanism suggested that CDK 15 facilitated CRC tumorigenesis by phosphorylating PAK4 at the S291 residue ( 37 ). However, which is not consistent with the information analysis based on the existing databases, So more studies are needed to verify this result.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of Role of Cyclin-Dependent Kinases Family Members in Colorectal Cancer

Guan

Tang

et al. 2022

Front. Oncol.

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BackgroundCyclin-dependent kinases (CDKs) are cell cycle regulators, and abnormal activation can accelerate tumor cell proliferation. However, The relation between CDKs dysregulation to colorectal cancer incidence and progression have not been examined in detail. Methods:Differences in CDKs expression between colorectal cancer and normal tissues, associations between expression and clinical prognosis, incidence and frequencies of CDKs gene mutations, and the influences of CDKs on tumor infiltration by immune cells were examined by analyses of Oncomine, Gene Expression Profiling Interactive Analysis, Kaplan-Meier plotter, cBioPortal, GeneMANIA, and TIMER databases.ResultsColorectal cancer tissues showed enhanced expression levels of CDKs 1/2/4/5/6/8/12/13/19 but reduced CDK3 expression. CDK7 was highly expressed in some colorectal cancer tissues but downregulated in others. Expression levels of CDK1/3/4/7/8/10/11b/13/18/19/20 were correlated with clinical stage, and CDK 5/10/12/16 expression levels predicted prognosis and survival. Differential CDKs expression correlated with cell cycle progression, amino acid polypeptide modifications, and activation of other protein kinases. Expression levels of all CDKs except CDK16 were correlated with infiltration of CD4+T, CD8+T, B and Tregs cells.ConclusionsCDK 1 and 4 could be used as diagnostic biomarkers for CRC. CDK 5/10/12/16 can be utilized as prognostic biomarkers.

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“…Substitution of atoms in the small molecules might, depending on their properties, change their physicochemical properties or affect the bioavailability and efficacy of bioactive molecules [ 5 , 6 ]. Overexpression or activation of the target protein PAK4 is often associated with cancer and oncogenic transformation [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. In a previous study, we found a small-molecule compound with biological inhibition of PAK4 with a unique scaffold [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

“…Here, p21-activated kinase 4 (PAK4) protein was selected as the target protein. PAK4 overexpression or activation in human tissues is often associated with cancer and oncogenic transformation [ 9 , 10 , 11 , 12 ]. PAK4 overexpression correlates with various cancers, including breast cancer [ 13 ], ovarian cancer [ 14 ], pancreatic cancer [ 15 ], prostate cancer [ 16 ], gastric cancer [ 17 ], and gliomas [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

A Study on the Effect of the Substituent against PAK4 Inhibition Using In Silico Methods

Yoon

Chai²,

Kim³

et al. 2022

IJMS

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The intrinsic inductive properties of atoms or functional groups depend on the chemical properties of either electron-withdrawing groups (EWGs) or electron-donating groups (EDGs). This study aimed to evaluate in silico methods to determine whether changes in chemical properties of the compound by single atomic substitution affect the biological activity of target proteins and whether the results depend on the properties of the functional groups. We found an imidazo[4,5-b]pyridine-based PAK4 inhibitor, compound 1, as an initial hit compound with the well-defined binding mode for PAK4. In this study, we used both experimental and in silico methods to investigate the effect of atomic substitution on biological activity to optimize the initial hit compound. In biological assays, in the case of EWG, as the size of the halogen atom became smaller and the electronegativity increased, the biological activity IC50 value ranged from 5150 nM to inactive; in the case of EDG, biological activity was inactive. Furthermore, we analyzed the interactions of PAK4 with compounds, focusing on the hinge region residues, L398 and E399, and gatekeeper residues, M395 and K350, of the PAK4 protein using molecular docking studies and fragment molecular orbital (FMO) methods to determine the differences between the effect of EWG and EDG on the activity of target proteins. These results of the docking score and binding energy did not explain the differences in biological activity. However, the pair-interaction energy obtained from the results of the FMO method indicated that there was a difference in the interaction energy between the EWG and EDG in the hinge region residues, L398 and E399, as well as in M395 and K350. The two groups with different properties exhibited opposite electrostatic energy and charge transfer energy between L398 and E399. Additionally, we investigated the electron distribution of the parts interacting with the hinge region by visualizing the molecular electrostatic potential (MEP) surface of the compounds. In conclusion, we described the properties of functional groups that affect biological activity using an in silico method, FMO.

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CDK15 promotes colorectal cancer progression via phosphorylating PAK4 and regulating β-catenin/ MEK-ERK signaling pathway

Cited by 35 publications

References 44 publications

Synergistic Antitumoral Effect of Epigenetic Inhibitors and Gemcitabine in Pancreatic Cancer Cells

Synergistic Antitumoral Effect of Epigenetic Inhibitors and Gemcitabine in Pancreatic Cancer Cells

Comprehensive Analysis of Role of Cyclin-Dependent Kinases Family Members in Colorectal Cancer

A Study on the Effect of the Substituent against PAK4 Inhibition Using In Silico Methods

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