Selective CDK7 inhibition with BS-181 suppresses cell proliferation and induces cell cycle arrest and apoptosis in gastric cancer

Wang, Bo-Yong; Liu, Quanyan; Cao, Jun; Chen, Jiwei; Liu, Zhisu

doi:10.2147/dddt.s86317

Cited by 37 publications

(34 citation statements)

References 20 publications

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“…33 Wang et al explained that CDK7 inhibition hindered cell proliferation and promoted cell apoptotic rate in GC. 34 Coincidently, in the present study, CDK7 was identified as a target of miR-33a-5p. Our studies further showed that CDK7 knockdown attenuated the promotion impacts of anti-miR-33a-5p on GC cell proliferation, metastasis, and the inhibition effect of that on GC cells apoptosis.…”

Section: Discussionsupporting

confidence: 72%

<p>Gambogic Acid Inhibits the Progression of Gastric Cancer via circRNA_ASAP2/miR-33a-5p/CDK7 Axis</p>

Lin¹,

Lin²,

He³

et al. 2020

CMAR

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Background: Gastric cancer (GC) is a major cancer-related mortality disease. Gambogic acid (GA) has been investigated to inhibit cancer progression. In the present study, the molecular mechanism of GA in regulating GC progression was studied. Methods: The expression levels of circular RNA ASAP2 (circ_ASAP2), miR-33a-5p and cyclin-dependent kinases 7 (CDK7) were detected by quantitative real-time polymerase reaction (qRT-PCR). CDK7 protein level was evaluated by Western blot. Cell colony formation assay, 3-(4,5-Dimethylthazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, transwell assay and flow cytometry analysis were employed to reveal the functional effects among circ_ASAP2, miR-33a-5p and CDK7 on GA-induced GC progression. Mechanistically, the binding relationship between miR-33a-5p and circ_ASAP2 or CDK7 was predicted with starBase v3.0 online database and verified by dual-luciferase reporter assay. In vivo tumor formation assay was used to explain the impacts of GA treatment on GC growth in vivo. Results: Circ_ASAP2 and CDK7 expression were downregulated in GA-induced GC cells compared with GC cells. MiR-33a-5p expression was upregulated in GA-induced GC cells relative to GC cells. The protein expression level of CDK7 was lower in GA-induced GC cells than that in GC cells. Further, circ_ASAP2 overexpression decreased GA-induced inhibition effects on cell proliferation, migration and invasion and GA-induced promotion effect on cell apoptosis in both AGS and HGC-27 cells, whereas this phenomenon was reversed by miR-33a-5p. In addition, circ_ASAP2 functioned as a sponge of miR-33a-5p and miR-33a-5p was associated with CDK7. Furthermore, GA treatment inhibited GC growth in vivo. Conclusion: Circ_ASAP2 overexpression promoted cell proliferation, migration and invasion, whereas inhibited cell apoptosis by upregulating CDK7 expression through binding to miR-33a-5p in GA-induced GC cells. This study provided a theoretical basis in GC treatment with GA.

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Section: Discussionsupporting

confidence: 72%

<p>Gambogic Acid Inhibits the Progression of Gastric Cancer via circRNA_ASAP2/miR-33a-5p/CDK7 Axis</p>

Lin¹,

Lin²,

He³

et al. 2020

CMAR

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“…10,18 In summary, our study showed for the first time that THZ1 may exert its anticarcinogenic effect in HCC cells both in vitro and in vivo in HCC mouse model: (a) inhibiting rapid proliferation of HCC cells; (b) promoting the apoptosis of HCC cells. Thus, THZ1 induced apoptosis by the prolonged CDK7 inhibition in HCC cells.…”

Section: Discussionmentioning

confidence: 67%

Inhibition of cyclin‐dependent kinase 7 suppresses human hepatocellular carcinoma by inducing apoptosis

Zhong

Yang

Jia

et al. 2018

J of Cellular Biochemistry

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Increasing evidence has shown that THZ1, a covalent cyclin-dependent kinase 7 (CDK7) inhibitor, exhibits therapeutic effects in various tumors. However, the possible effect of THZ1 on hepatocellular carcinoma (HCC) remains unknown. Our study was to investigate the roles of THZ1 in HCC cells and in subcutaneous HCC model and illustrate the molecular mechanisms. The phosphorylation levels of Ser2, Ser5, and Ser7 within RNA polymerase II (RNAPII) C-terminal domain (CTD) and the expression levels of Ki67, Mcl-1, survivin, XIAP, and p53 in HCC cells under different conditions were examined by Western blot analysis. Cell growth and apoptosis were assessed via 3-(4,5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assay and flow cytometry analysis, respectively. Tumor volume was assessed in HCC mice with THZ1 or vehicle treatment and immunohistochemical (IHC) analysis was conducted on excised tumors. THZ1 significantly inhibited the phosphorylation of Ser2, Ser5, and Ser7 within RNAPII-CTD in the dose-dependent and irreversible manner. MTT assay and flow cytometry analysis showed that THZ1 inhibited HCC cell proliferation and induced apoptosis, respectively. Western blot analysis indicated THZ1 significantly upregulated p53 expression and downregulated the expressions of Mcl-1, survivin, XIAP, and Ki67. THZ1 suppressed tumor growth in Hep3B xenografted mice in a time-dependent manner. IHC analysis indicated that tumors in THZ1 group had less Ki67+ cells and more cleaved caspase-3+ cells than those in vehicle group. THZ1 exhibited anti-HCC effects through irreversibly inhibiting CDK7 activity, decreasing RNAPII-CTD phosphorylation, inducing p53 expression and inhibiting antiapoptotic gene expressions, which subsequently induced apoptosis and inhibited proliferation of HCC cells.

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“…On the other hand, a challenging problem for the development and use of drugs that target nuclear factors is to increase the permeability of these compounds in the nucleus. The treatment with TPL or THZ1 cause an important reduction in transcription in cancer cell lines, showing that an important amount of these molecules permeates the nuclear membrane 4,44,45, however more precise experiments with animal models are needed. In addition, new methods to increase the efficiency to deliver new drugs to the nucleus still have to be developed.…”

Section: Discussionmentioning

confidence: 99%

“…Although other TPL targets have been proposed, structural and biochemical data show that it is very specific for XPB, and intriguingly, the treatment of Drosophila imaginal discs with TPL phenocopies the defects observed in different TFIIH mutant subunits in the fly 41-43. RNA-seq and DNA microarray analyses from TPL-treated cancerous cells have shown the down-regulation of nearly all the RNAPII-dependent transcripts 44,45; however, comparative studies at this level between cancer cells and their progenitors are required. TPL is not highly permeable to the cell membrane, and it is hepatotoxic 46.…”

Section: Tfiih As a Target For Cancer Therapymentioning

confidence: 99%

“…For example, the antitumor drug BS-181 is a pyrazolo [1,5-a] pyrimidine-derived compound that inhibits the phosphorylation of Cdk7 targets, inducing cell cycle arrest and apoptosis 45. More recently, it was shown that THZ1 is a phenylaminopyrimidine with a cysteine reactive acrylamide moiety that covalently binds to the cysteine 312 located outside of the catalytic domain, making THZ1 very specific for Cdk7 20, although it inhibits Cdk12 at very high concentrations and after long incubation times 36.…”

Section: Tfiih As a Target For Cancer Therapymentioning

confidence: 99%

See 1 more Smart Citation

TFIIH: New Discoveries Regarding its Mechanisms and Impact on Cancer Treatment

Zurita¹,

Cruz‐Becerra²

2016

J. Cancer

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The deregulation of gene expression is a characteristic of cancer cells, and malignant cells require very high levels of transcription to maintain their cancerous phenotype and survive. Therefore, components of the basal transcription machinery may be considered as targets to preferentially kill cancerous cells. TFIIH is a multisubunit basal transcription factor that also functions in nucleotide excision repair. The recent discoveries of some small molecules that interfere with TFIIH and that preferentially kill cancer cells have increased researchers' interest to elucidate the complex mechanisms by which TFIIH operates. In this review, we summarize the knowledge generated during the 25 years of TFIIH research, highlighting the recent advances in TFIIH structural and mechanistic analyses that suggest the potential of TFIIH as a target for cancer treatment.

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Selective CDK7 inhibition with BS-181 suppresses cell proliferation and induces cell cycle arrest and apoptosis in gastric cancer

Cited by 37 publications

References 20 publications

<p>Gambogic Acid Inhibits the Progression of Gastric Cancer via circRNA_ASAP2/miR-33a-5p/CDK7 Axis</p>

<p>Gambogic Acid Inhibits the Progression of Gastric Cancer via circRNA_ASAP2/miR-33a-5p/CDK7 Axis</p>

Inhibition of cyclin‐dependent kinase 7 suppresses human hepatocellular carcinoma by inducing apoptosis

TFIIH: New Discoveries Regarding its Mechanisms and Impact on Cancer Treatment

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