<scp>CDK</scp>7 inhibition suppresses rheumatoid arthritis inflammation <i>via</i> blockage of <scp>NF</scp>‐κB activation and <scp>IL</scp>‐1β/<scp>IL</scp>‐6 secretion

Hong, Honghai; Zeng, Yingmin; Jian, Wenxuan; Li, Lei; Lin, Li‐Ying; Mo, Yousheng; Liu, Meiling; Fang, Shuhuan; Xia, Yong

doi:10.1111/jcmm.13414

Cited by 27 publications

(16 citation statements)

References 39 publications

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“…In the present study, the serum levels of 14-3-3η were positively correlated with RF and ACPA levels in Chinese patients with RA, which was partially consistent with the above-mentioned studies. This consistency may be due to the fact that 14-3-3η, RF and ACPA are all involved in the release of pro-inflammatory factors, including IL-1β and IL-6, which are correlated with inflammation in RA (34)(35)(36). Therefore, it was expected for 14-3-3η serum levels to exhibit a positive correlation with RF and ACPA levels in patients with RA in the present study.…”

Section: Discussionsupporting

confidence: 52%

Serum levels of 14‑3‑3η are associated with increased disease risk, activity and duration of rheumatoid arthritis in Chinese patients

Chen

Dai

et al. 2020

Exp Ther Med

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The aim of the present study was to determine the association between serum 14-3-3η expression levels and disease risk, inflammation level and disease duration in Chinese patients with rheumatoid arthritis (RA). A total of 45 Chinese patients with RA, 45 patients with osteoarthritis (OA) and 44 age- and sex-matched (with the RA group) healthy control (HC) subjects were consecutively recruited for the present case-controlled study. In addition, the demographic and clinicopathological characteristics of the patients with RA were collected. Serum samples were obtained from patients with RA, patients with OA and the HCs, and the serum levels of 14-3-3η were determined by ELISA. Compared with that in the OA patients (P=0.006) and HCs (P<0.001), 14-3-3η expression was significantly increased in RA patients, and receiver operating characteristics (ROC) analysis indicated that it served as a potential predictive marker for the risk of RA. In patients with RA, serum levels of 14-3-3η were positively correlated with disease duration (P=0.003), erythrocyte sedimentation rate (P=0.006) and disease activity score in 28 joints (P=0.025). The proportion of rheumatoid factor (RF)-positive patients (P=0.023) and anti-citrullinated protein antibody (ACPA)-positive patients (P=0.002) with RA was increased (when 14-3-3η expression was increased) compared with RF-negative patients or ACPA-negative patients, respectively. Of note, 14-3-3η serum levels were able to distinguish patients with established RA (disease duration, >2 years) from patients with early RA (disease duration, ≤2 years) with an AUC of 0.759 (95% CI, 0.612-0.905), and the sensitivity and the specificity at the best cut-off point (14-3-3η=0.613 ng/ml) were 79.3 and 75.0%, respectively. Furthermore, 14-3-3η was able to differentiate between RF-positive RA patients and RF-negative patients or HCs. In conclusion, circulating 14-3-3η expression may serve as a novel biomarker for disease risk and activity of RA in Chinese patients.

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Section: Discussionsupporting

confidence: 52%

Serum levels of 14‑3‑3η are associated with increased disease risk, activity and duration of rheumatoid arthritis in Chinese patients

Chen

Dai

et al. 2020

Exp Ther Med

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“… 45 Our results following knockdown of CDK7 by RNAi are therefore significant, especially given the pronounced decrease in cell proliferation and migration, and increased apoptosis that mirror the effects reported in other vulnerable cancers. 15 , 38 , 46 …”

Section: Discussionmentioning

confidence: 99%

RETRACTED: Cyclin-dependent kinase 7 (CDK7) is an emerging prognostic biomarker and therapeutic target in osteosarcoma

Dean

Wei

et al. 2021

Therapeutic Advances in Musculoskeletal

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Background: Overexpression of cyclin-dependent kinase 7 (CDK7) is a well-known pathogenic feature of various malignancies and a sign of a more dismal prognosis. As relatively little is known about CDK7 in osteosarcoma, we elected to evaluate its expression, prognostic value, and function. Methods: We began by analyzing the publicly available data sets on CDK7 expression, including RNA sequencing data from the Therapeutically Applicable Research to Generate Effective Treatments on Osteosarcoma (TARGET-OS) and the Gene Expression database of Normal and Tumor tissues 2 (GENT2). The correlation between patient tissue CDK7 expression and their clinicopathological features and prognosis was assessed via immunohistochemical staining of a unique tissue microarray constructed from osteosarcoma specimens. Furthermore, we analyzed CDK7 expression in osteosarcoma cell lines and tissues by Western blot. CDK7-specific siRNA and a highly-selective CDK7 inhibitor, BS-181, were applied to determine the function of CDK7 on osteosarcoma cell growth and proliferation. In addition, the effect of CDK7 inhibition on clonogenicity was evaluated using a clonogenic assay, and a 3D cell culture model was used to mimic CDK7 effects in an in vivo environment. Results: Our results demonstrate that higher CDK7 expression significantly correlates with recurrence, metastasis, and shorter overall survival in osteosarcoma patients. Therapeutically, we show that CDK7 knockdown with siRNA or selective inhibition with BS-181 decreases proliferation and induces apoptosis of osteosarcoma cells. Conclusion: This study supports CDK7 overexpression as an independent predictor of poor prognosis and promising therapeutic target for osteosarcoma.

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“…This suggests that the inhibition of Erk, a kinase known to be involved in the regulation of cytokine expression (46, 47), could mediate this effect. In addition, inhibition of Cdk7 by a specific inhibitor (BS-181) and siRNA-Cdk7 knockdown has already been demonstrated to reduce IL-1 β , IL-6, IL-8 transcript levels, and IL-1β/IL-6 secretion in LPS-induced MH7A cells (48), suggesting that the inhibition of Cdk7 may also be involved.…”

Section: Discussionmentioning

confidence: 99%

Cdk5 Deletion Enhances the Anti-inflammatory Potential of GC-Mediated GR Activation During Inflammation

et al. 2019

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The suppression of activated pro-inflammatory macrophages during immune response has a major impact on the outcome of many inflammatory diseases including sepsis and rheumatoid arthritis. The pro- and anti-inflammatory functions of macrophages have been widely studied, whereas their regulation under immunosuppressive treatments such as glucocorticoid (GC) therapy is less well-understood. GC-mediated glucocorticoid receptor (GR) activation is crucial to mediate anti-inflammatory effects. In addition, the anti-cancer drug roscovitine, that is currently being tested in clinical trials, was recently described to regulate inflammatory processes by inhibiting different Cdks such as cyclin-dependent kinase 5 ( Cdk5 ). Cdk5 was identified as a modulator of inflammatory processes in different immune cells and furthermore described to influence GR gene expression in the brain. Whether roscovitine can enhance the immunosuppressive effects of GCs and if the inhibition of Cdk5 affects GR gene regulatory function in innate immune cells, such as macrophages, has not yet been investigated. Here, we report that roscovitine enhances the immunosuppressive Dexamethasone (Dex) effect on the inducible nitric oxide synthase (iNos) expression, which is essential for immune regulation. Cdk5 deletion in macrophages prevented iNos protein and nitric oxide (NO) generation after a combinatory treatment with inflammatory stimuli and Dex. Cdk5 deletion in macrophages attenuated the GR phosphorylation on serine 211 after Dex treatment alone and in combination with inflammatory stimuli, but interestingly increased the GR-dependent anti-inflammatory target gene dual-specificity phosphatase 1 (Dusp1, Mkp1). Mkp1 phosphatase activity decreases the activation of its direct target p38Mapk, reduced iNos expression and NO production upon inflammatory stimuli and Dex treatment in the absence of Cdk5 . Taken together, we identified Cdk5 as a potential novel regulator of NO generation in inflammatory macrophages under GC treatment. Our data suggest that GC treatment in combination with specific Cdk5 inhibtior(s) provides a stronger suppression of inflammation and could thus replace high-dose GC therapy which has severe side effects in the treatment of inflammatory diseases.

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CDK7 inhibition suppresses rheumatoid arthritis inflammation via blockage of NF‐κB activation and IL‐1β/IL‐6 secretion

Cited by 27 publications

References 39 publications

Serum levels of 14‑3‑3η are associated with increased disease risk, activity and duration of rheumatoid arthritis in Chinese patients

Serum levels of 14‑3‑3η are associated with increased disease risk, activity and duration of rheumatoid arthritis in Chinese patients

RETRACTED: Cyclin-dependent kinase 7 (CDK7) is an emerging prognostic biomarker and therapeutic target in osteosarcoma

Cdk5 Deletion Enhances the Anti-inflammatory Potential of GC-Mediated GR Activation During Inflammation

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