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Nuclear Factor Kappa-B: Bridging Inflammation and Cancer
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Mohammad Aslam Khan, Girijesh Kumar Patel, Haseeb Zubair, Nikhil Tyagi, Shafquat Azim, Seema Singh, Aamir Ahmad, Ajay Pratap Singh
Inhibition of NF-κB activation could be achieved by inhibiting kinase activity of IKK with the specific inhibitors of IKKα and/or IKKβ. Irreversible inhibitors, BAY 11-7082 and BAY 11-7085, block phosphorylation of IκBα, suppress proteasomal degradation of IκBα and inhibit NF-κB translocation to the nucleus. In vitro study suggested that BAY 11-7082 treatment blocks NF-κB activation and induces mitochondrial mediated apoptosis. Treatment with BAY 11-7082 downregulated the expression of cyclin A and CDK-2 and induced cell cycle arrest [155]. Another study suggested that BAY 11-7082 induces robust cell death in primary adult leukemic T cells, as compared to normal peripheral blood mononuclear cells (PBMCs), by inhibiting the activation of NF-κB [156]. BAY 11-7085 treatment potentiates the efficacy of cisplatin in ovarian cancer by downregulating the expression of X-linked inhibitor of apoptosis protein (XIAP) and suppressing tumor cell invasiveness [157]. Pham and colleagues suggested that BAY 11-7082 treatment blocked constitutive activation of NF-κB, and induced apoptosis in non-Hodgkin mantle cell lymphoma by downregulating expression of Bcl-XL and Bfl/A1 [158]. In pre-clinical study, it has been shown that colon cancer cells-bearing mice treated with BAY 11-7085 fail to develop tumor, as compared to vehicle treated mice [159]. Co-administration of BAY11-7085 with histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), reduces NF-κB in non-small cell lung cancer cells and induces enhanced apoptosis, as compared to single treatment [160].
Regulation of Airway Smooth Muscle Proliferation by β2-Adrenoceptor Agonists
Published in Alastair G. Stewart, AIRWAY WALL REMODELLING in ASTHMA, 2020
Alastair G. Stewart, Paul R. Tomlinson, Leslie Schachte
In mammalian cells there is a point in late G1 after which the cell cycle proceeds to DNA synthesis without the requirement of the continued presence of mitogenic stimulation or despite the addition of certain inhibitors of mitogenesis. The molecular gate that constitutes the restriction point is believed to be underphosphorylated retinoblastoma protein (Rb). Mitogenic stimulation activates the transcription of cyclins and cyclin-dependent kinases (Cdks). Cyclins and Cdks form complexes which are then phosphorylated by a cyclin-activating kinase (CAK). Activated cyclin–Cdk complexes appear in mid G1 and are responsible for the phosphorylation of the tumor suppressor gene product, Rb. Hypophosphorylated Rb is normally bound to the transcription factor E2F, inhibiting transcriptional activity. Phosphorylation of Rb bycyclin–Cdk complexes is a key event prior to the G1 restriction point, resulting in the dissociation of Rb from E2F, allowing the transcription of genes required for progression through S phase and DNA synthesis. A number of inhibitors of mitogenesis appear to act by interfering with the signalling step(s) that precede the dissociation of inhibitory proteins from the E2F complex.
Alteration in Cell Cycle Control Factors and the Induction of Oxygen-Regulated Proteins by Hypoxic Stress
Published in John J. Lemasters, Constance Oliver, Cell Biology of Trauma, 2020
Harold C. Smith, Robert L. Howell, John W. Ludlow
The trivial explanation for this effect, namely, that pRB phosphorylation state in hypoxic cells simply reflects the reduced energy charge of the cells, does not appear to be the complete story. Cyclin A belongs to a family of proteins known as cyclins, the primary function of which appears to be modulation of the activities of specific kinases and cell cycle regulatory factors through a direct interaction.45,47,51,52 Cyclin A and its interactions appear to be important for S phase progression. This protein is rapidly synthesized during S phase and subsequently rapidly degraded as a prerequisite to M phase progression. Cyclin A is targeted for proteolysis through an ATP-dependent phosphorylation.53 If the loss of energy charge in hypoxic cells was strictly responsible for pRB hypophosphorylation, then it would be anticipated that cyclin A could not be degraded. In contrast, the data show that cyclin A is rapidly lost from hypoxic cells and is not resynthesized until the cells are reoxygenated (Figures 3 and 4). These data suggest that hypoxia may impair cell cycle progression by specifically affecting control through key cell cycle regulatory factors. It is also of interest that alterations in the phosphorylation state of pRB and the turnover of cyclin A in hypoxic cells appear to be uncoupled from the requirement that cells overtly progress through the cell cycle in response to these changes.
Metformin induces myeloma cells necrosis and apoptosis and it is considered for therapeutic use
Published in Journal of Chemotherapy, 2023
Zhentian Wu, Lianghua Wu, Liangliang Zou, Muqing Wang, Xin Liu
In our study, cellular and molecular mechanisms responsible for the actions of metformin differed from cell line to cell line. For U266 cells, it induced necrosis. For H929, RPMI8226, and MM.1s cells, it induced apoptosis. Cell cycle analysis showed that the cycle arrest also varied from cell to cell following metformin treatment. We found no change in U266 cells, in H929 and MM.1s cells, it induced at the G0/G1 phase, and in RPMI8226, it induced at the G2/M phase. Cell cycle arrest is controlled by some cyclin-dependent kinases (CDKs), such as cyclin-D1 in the G1/S transition and cyclin-B1 in the G2/M transition. We hypothesize that metformin acts powerfully on the cell cycle via different pathways in different MM cells. For H929 and MM.1s cells, the down-regulation of CyclinD1 leads to G1/G0 arrest and suppresses the cell proliferation. Cyclin-B1 is a key regulator of the cell cycle, it is involved in regulating the events of mitosis. It increased in the early G2 phase, and it is necessary for transition from G2 to M. Here we show that RPMI8226 cells arrested in G2/M with down-regulation of cyclin-B1 while metformin treated. It suggests that this reduction leads to accumulation of MM cells in the G2 phase and inhibits transition to the M phase. Necrosis is an unordered and accidental form of cellular dying, and usually with no changes in cell cycle arrest. For U266, we found necrosis related protein iNOS increasingly expressed and no apoptosis-associated protein was detected. It further confirmed that metformin might induce U266 necrosis.
Development of newly synthesised quinazolinone-based CDK2 inhibitors with potent efficacy against melanoma
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Eman R. Mohammed, Ghada F. Elmasry
Cyclin-dependent kinase 2 (CDK2) is a key regulator of the cell cycle transition and progression. CDK2 performs a critical role in controlling various events of the cell division cycle, such as DNA repair, gene transcription, G1-S transition, and modulation of G2 progression6–8. Additionally, the altered expression of cyclins whose association with CDKs is essential for their catalytic activity can drive aberrant proliferation in cancer. In the same vein, the overexpression of CDK2 regulatory subunits cyclin A and/or E is a key oncogenic process in many types of cancers9,10. Owing to the crucial role of CDK2 in cell cycle regulation, transcription activity, and tumours epigenetic modifications, CDK2 inhibition may confer a therapeutic benefit against certain cancers viz breast cancer11, colo-rectal cancer12,13, glioblastoma14–16, and melanoma17,18.
Benzo(a)pyrene affects proliferation with reference to metabolic genes and ROS/HIF-1α/HO-1 signaling in A549 and MCF-7 cancer cells
Published in Drug and Chemical Toxicology, 2022
Meili Gao, Aqun Zheng, Lan Chen, Fan Dang, Xiaojing Liu, Jianghong Gao
The proliferation of cancer cells is associated with the proportion of cells that enter the cell cycle. Our results were similar to those of previous reports, which showed that BaP exposure caused S phase arrest, with enlarged cell sizes in A549 cells (Wang et al. 2009) and lengthened the S phase interval, resulting in G2/M accumulation in MCF-7 cells (Jeffy et al.2000). The results of the present study indicated the induction of cell cycle progression in the examined cancer cell lines. Cell cycle progression is regulated by interactions between cyclins and CDKs. The cyclin A–CDK2 interaction activates DNA synthesis and promotes DNA replication and is essential for the G1⁄S phase transition and progression through the S phase (Copeland et al. 2015). Mitosis is triggered by the activation of CDK1/cyclin B, also known as M-phase promoting factor (Ma et al.2016). A previous study reported that BaP exposure increased the expression levels of cyclin D1, CDK4, and CDK2, but no change in cyclin A expression was reported in A549 cells (Wang et al.2009). Our findings provided evidence for CDK1-cyclin B involvement in the regulation of the BaP-mediated effects on cell cycle progression in A549 cells. We also demonstrated that cyclin A-CDK2 and CDK1-cyclin B are strongly involved in the regulation of the BaP-mediated effects on the cell cycle progression of MCF-7 cells. To the best of our knowledge, the findings of increased CDK1 and cyclin B expression induced by BaP in A549 and MCF-7 cell lines have not been previously reported in the literature.