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Effects of Retinoids at the Cellular Level (Differentiation, Apoptosis, Autophagy, Cell Cycle Regulation, and Senescence)
Published in Ayse Serap Karadag, Berna Aksoy, Lawrence Charles Parish, Retinoids in Dermatology, 2019
In addition, cell cycle progression upon treatment with RA is dependent on the cyclin family of proteins, in particular Cyclin C expression. As a partner of cyclin-dependent kinase 3 (CDK3), Cyclin C controls cellular proliferation and, together with CDK8, represses gene transcription. Cyclin C gene is a direct target for RA in HEK293 human embryonal kidney cells, containing two RAR binding sites (88).
Circulating tumor cells and circulating tumor DNA in precision medicine
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
The use of a CTC-chip in patients with metastatic small-cell lung cancer to detect for EGFR mutation states has also been reported. Monitoring of CTC cells revealed that the attainment of recurrent T790M-EGFR drug resistance mutation coincided with development of clinically refractory disease (Maheswaran et al., 2008). Similarly, use of a CTC-iChip for RNA sequencing on a breast CTC cluster led to the discovery of plakoglobin that helps in the maintenance of CTC clusters (Aceto et al., 2014). Now with the availability of genome-wide analysis strategies, use of array-CGH and NGS can reveal all possible mechanisms of resistance instead of analyzing only specific previously known mutations (Heitzer et al., 2013a). In a whole exome sequencing of two prostate cancer patients, CTCs revealed 70% overlap with mutations found in lymph node metastasis and primary tissue (Lohr et al., 2014). CTCs also showed heterogeneity in the TP53, PIK3CA, ESR1, and KRAS genes. Further, it is also suggested that we can study other relevant features of the tumor genome not present or observed during earlier initial diagnosis. This was observed in a patient where CTC examination at 34 and 24 months after diagnosis of primary tumor and liver metastasis revealed high amplification of CDK8 not found earlier (Heitzer et al., 2013a). Such critical identification has led to identification of viable targets for therapy (in the aforementioned case use of CDK inhibitors) (Dickson et al., 2010; Wang and Ren, 2010; Ramaswamy et al., 2012).
Personalized Medicine in Lung Cancer
Published in II-Jin Kim, Cancer Genetics and Genomics for Personalized Medicine, 2017
Daniela Morales-Espinosa, Silvia Garcá-Román, Rafael Rosell
Many drugs target CDKs as these are deregulated in cancer cells. Their inhibitors compete with ATP for the enzyme active site. Therefore, CDK inhibition results in RNPII hypophosphorylation.51 The most commonly targeted CDKs are CDK7, CDK8 and CDK9. CDK7 is a component of basal transcription factor TFIIH that phosphorylates Serine 5 and 7 in the C-terminal domain (CTD) of the RNPII, which is important for promoter escape and recruitment of mRNA processing machinery during transcription.52 CDK9 is also a component of P-TEFb, which, similar to CDK7, phosphorylates CTD of RNPII at serine 2 for transcription elongation.53, 54 The same activity is observed with the CDK8 kinase, which phosphorylates CTD of RNPII, resulting in inhibition of transcription initiation complex.
Cyclin-dependent kinase inhibitors for the treatment of lung cancer
Published in Expert Opinion on Pharmacotherapy, 2020
Angel Qin, Haritha G. Reddy, Frank D. Weinberg, Gregory P. Kalemkerian
In the majority of human tissues, cells exit the cell cycle and are maintained in the quiescent G0 state. Normal cells must reenter the cell cycle to maintain physiologic levels of proliferation and ensure tissue renewal. Cyclin-dependent kinases (CDKs) are critical regulators of many components of the cell cycle (Figure 1). In general, CDK1 mediates mitotic progression, while CDK2 is recognized for its importance in DNA replication. CDK4 and CDK6 (CDK4/6) regulate growth factor signaling that drives cell cycle progression from G0 or G1 into S phase [1]. Both CDK4 and CDK6 have similar biological activity. While CDK1, CDK2, CDK4 and CDK6 directly promote cell cycle progression, other CDKs, such as CDK7, CDK8 and CDK9, regulate transcription. Given the importance of CDK4/6 in tumorigenesis and their potential as targets for anti-cancer therapy, this review will primarily focus on these kinases.
Mechanism of tumor cells escaping from immune surveillance of NK cells
Published in Immunopharmacology and Immunotoxicology, 2020
Zhe Ge, Shan Wu, Zhe Zhang, Shuzhe Ding
Cyclin-dependent kinase 8 (CDK8), a member of the transcription-regulating CDK family, contributes to the activation or repression of transcription by phosphorylating multiple transcription factors [109]. CDK8 plays a negative role in regulating the NK cell cytotoxicity. It has been observed that after specific knockout of CDK8 expression in NK cells, their cytotoxicity action on tumor cells increases [110]. More specifically, although STAT1 signaling contributes to NK cell cytotoxicity [35], CDK8-mediated S727 phosphorylation of STAT1 restrains NK cell cytotoxicity and tumor surveillance [109]. Moreover, CDK8 phosphorylates Smad, the essential downstream mediators of TGF-β signaling [111], which means that CDK8 may inhibit NK cell cytotoxicity by activating TGF-β signaling. In addition, enhancer of zeste homolog 2 (Ezh2), a histone methyltransferase related to gene repression, deletion or inhibition of its activity up-regulates the IL-15 receptor (IL-15R) and NKG2D expression on NK cells and their cytotoxicity to tumor cells [112]. However, the loss of CDK8 in intestinal cells and tumors leads to lower the activity of Ezh2, resulting in the decrease of histone H3K27 trimethylation [113]. Based on the above findings, CDK8 may inhibit NK cell function by activating TGF-β signal transduction and promoting H3K27 trimethylation, but the specific molecular mechanism is still unclear.
Evaluation of multikinase inhibitor LDN193189 induced hepatotoxicity in teleost fish Poecilia latipinna
Published in Drug and Chemical Toxicology, 2019
Isha Ranadive, Sonam Patel, Abhilasha Mhaske, Gowri Kumari Uggini, Isha Desai, Suresh Balakrishnan
The use of kinase inhibitor as a prospective drug in combating cancers of diverse type, at least on an experimental scale, is gaining momentum. Dasatinib, a multikinase inhibitor targeting BCR/ABL and Src tyrosine kinases, blocks epithelial ovarian cancer (EOC) cell invasion and induces apoptosis (Konecny et al.2009). Recently, McDermott et al. (2017) have found that CDK8 inhibition by CDK8/19-selective small molecule kinase inhibitors, via shRNA knockdown or CRISPR/CAS9 knockout suppresses estrogen-induced transcription in ER-positive breast cancer cells and hence can be beneficial for breast cancer therapy. Targeting kinases, therefore, have proven to be very useful as primary or adjuvant anticancer treatments. Therefore, small molecule inhibitors that affect multiple receptor kinases are being cited as a novel therapeutics for cancer (Zhang et al.2009).