Bacteria and Bioactive Peptides
Prakash Srinivasan Timiri Shanmugam in Understanding Cancer Therapies, 2018
Bacterial toxins have also been known to treat cancer by altering the cellular processes that maintain proliferation, apoptosis, and differentiation. Cytolethal distending toxins (CDTs) and the cycle-inhibiting factor (Cif) are cell-cycle inhibitors that block mitosis and compromise the immune system by inhibiting clonal expansion of lymphocytes. In contrast, the cytotoxic necrotizing factor (CNF), a cell-cycle stimulator, promotes cellular proliferation and interferes with cell differentiation (Nougayrede et al. 2005). CNF is a cell-cycle stimulator released by E. coli. CNF induces G1-S transition and causes DNA replication. CDTs are present in Campylobacter jejuni and S. typhi, while Cif is found in enteropathogenic (EPEC) and enterohemorrhagic (EHEC) E. coli. The anticancer activity of toxins shows reduced side effects compared to traditional treatments. Further the antitumor activity can be enhanced by combining bacterial toxins with anticancer drugs or irradiation (Carswell et al. 1975).
Senescent Cells as Drivers of Age-Related Diseases
Shamim I. Ahmad in Aging: Exploring a Complex Phenomenon, 2017
Progression through the cell cycle requires cells to pass cell cycle checkpoints, namely the G1-S transition, the S-phase checkpoint, the G2 to M transition, and the mitotic spindle checkpoint [26]. Replicative senescent cells become permanently arrested at G1 and G2 phases of the cell cycle [27,28]. Cellular senescence caused by telomere erosion evokes a DNA damage response (DDR), prompting the persistent activation of p53 via the ataxia telangiectasia mutated (ATM)/ATR DNA damage signaling pathway [29]. Upregulation of p21, a downstream effector of p53, is necessary to induce G1 cell cycle arrest following exposure to DNA-damaging agents [30]. Aside from triggering proliferative arrest in G1, p21 may also induce permanent G2 arrest in a number of senescent cells [31]. In contrast, loss of p21 causes DNA damaged cells to go through additional S-phases, resulting in polyploidy and subsequent apoptosis [32].
Molecular Biology of Lung Cancer as the Basis for Targeted Therapy
Kishan J. Pandya, Julie R. Brahmer, Manuel Hidalgo in Lung Cancer, 2016
Other TSGs frequently inactivated in lung cancer are retinoblastoma 1 (RB1) and CDKN2A (Table 2) (26). RB1 was the first TSG discovered after cytogenetic data suggested the position of a disease locus and Knudson proposed the two-hit hypothesis to explain the molecular mechanism responsible for the incidence patterns of hereditary and nonhereditary retinoblastoma in 1971. The gene was subsequently cloned in Weiberg’s laboratory in 1986. The active hypophosphorylated gene product, pRb, blocks the cell cycle at the G1/S transition. When progress through the cell cycle is triggered, pRb is hyperphosphorylated by specific kinases such as the CCND1/CDK4 complex. This allows the release of bound transcription factors and cell cycle progression. Recent data suggest that pRb also acts as a tumor survival factor. The CDKN2A gene product p16 inhibits CDK4 and stabilizes p53. The frequency of inactivation of RB1 or CDKN2A, either of which may lead to uncontrolled cell cycle progression, varies among histopathological subtypes of lung cancer. RB1, for example, is inactivated in almost all SCLCs, but uncommonly in NSCLC (Table 2).
miR-9 induces cell arrest and apoptosis of oral squamous cell carcinoma via CDK 4/6 pathway
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Anquan Shang, Wen-Ying Lu, Man Yang, Cheng Zhou, Hong Zhang, Zheng-Xin Cai, Wei-Wei Wang, Wan-Xiang Wang, Gui-Qi Wu
In this study, we confirmed the down-regulation of miR-9 in OSCC patients, followed by overexpressing miR-9 in the highly malignant OSCC cell line Tca8113, in which impaired cell growth, migration and ability to form colonies were observed. To specify the stages at which the cell growth were hampered, flow cytometry was employed to determine the cell count of each phase of cell cycle. As a consequence, a significantly elevated accumulation in G0/G1 phase cells and decrease in S phase cells indicated that G1/S transition was deterred. Among the top 100 candidate genes predicted through TargetScan, CDK6, a protein highly implicated in cell cycle control, was chosen for verification. Down-regulation of CDK6 and Cyclin D1 in Tca8113 transfected with miR-9 mimics indicate that the complex formed by both proteins may be the effector of the antiproliferative function of miR-9 in OSCCs.
Strategic development of AZD1775, a Wee1 kinase inhibitor, for cancer therapy
Published in Expert Opinion on Investigational Drugs, 2018
Siqing Fu, Yudong Wang, Khandan Keyomarsi, Funda Meric-Bernstein
The G1-S transition is controlled by a variety of parallel and cooperative pathways: Ras-c-Myc, Rb-E2F-cyclin E, and p53-p21 cascades. The convergence of these pathways controls the activity of Cdk2 at the G1-S boundary through Cdc25A degradation [1]. During the G1 phase, phosphorylation of pRb by D-CDKs releases E2F from the complex to induce expression of E2F-targeted genes such as cyclin E, facilitating cell cycle progression. Also, co-expression of Ras with c-Myc allows the generation of cyclin E-dependent kinase activity, coincident with the loss of the p27 CDK inhibitor before induction of S phase. These evidences support the concept that cyclin E serves as a key mediator of transition during the G1-S cellular division phase, which is deregulated in a wide variety of human cancers [15].
Effects of MFG-E8 expression on the biological characteristics of ovarian cancer cells via the AKT/mTOR/S6K signalling pathway
Published in Journal of Obstetrics and Gynaecology, 2023
Na Li, Yazhuo Wang, Lin Liu, Pei Wang, Xiaohua Wu
The G1/S phase transition of the cell cycle is controlled by cyclin-dependent protein kinases. The kinase-cyclin complex, which modulates the kinase activity, regulates cell cycle progression by targeted phosphorylation. The activity of these complexes peaks during the G1/S transition of the cell cycle and promotes cell mitosis (Lee et al.2019). Cyclin D mainly regulates the G1/S cell cycle transition, and its expression is closely related to the abnormal proliferation of tumours (Blain 2008). Besides, MFG-E8 could promote the proliferation of human pulmonary artery smooth muscle cells via p-Akt/cyclin D1 pathway (Wang et al.2021). Our present study showed consistent changes in cell proliferation and expression of cyclin D1 and CDK4 after MFG-E8 silence. Previous studies have focussed on the role of MFG-E8 in artery smooth muscle cells (VSMC) (Wang et al.2012, 2021), however, our study confirmed that MFG-E8 is involved in cell cycle regulation, which could help us better understand the mechanism of MFG-E8 in tumours.