Abstract:Background Deregulation of cell cycle takes place during the development of many cancers as well as pancreatic ductal adenocarcinoma (PDA), which develops from precursor lesions, most frequently including pancreatic intraepithelial neoplasia (PanIN). Aims The aim of this study was to evaluate and compare the expression of p16, p21, and p53 proteins taking part in the regulation of the cell cycle in normal pancreatic ducts and pancreatic intraepithelial neoplasia at its various advancing stages. Methods The exp… Show more
“…A crucial checkpoint, controlled by the CDK4/6-cyclin D-Rb pathway, is the transition from G1 to S phase [ 144 ]. Consequently, dysregulation of the Rb pathway results in enhanced proliferation [ 145 , 146 , 147 , 148 ]. Against the background of a high frequency of KRAS mutations, which is the case in PDAC, the CDK4/6 inhibitor encoding function of the CDKN2A locus is principally relevant [ 26 ].…”
Section: The Role Of Cdks In Pancreatic Cancermentioning
The family of cyclin-dependent kinases (CDKs) has critical functions in cell cycle regulation and controlling of transcriptional elongation. Moreover, dysregulated CDKs have been linked to cancer initiation and progression. Pharmacological CDK inhibition has recently emerged as a novel and promising approach in cancer therapy. This idea is of particular interest to combat pancreatic ductal adenocarcinoma (PDAC), a cancer entity with a dismal prognosis which is owed mainly to PDAC’s resistance to conventional therapies. Here, we review the current knowledge of CDK biology, its role in cancer and the therapeutic potential to target CDKs as a novel treatment strategy for PDAC.
“…A crucial checkpoint, controlled by the CDK4/6-cyclin D-Rb pathway, is the transition from G1 to S phase [ 144 ]. Consequently, dysregulation of the Rb pathway results in enhanced proliferation [ 145 , 146 , 147 , 148 ]. Against the background of a high frequency of KRAS mutations, which is the case in PDAC, the CDK4/6 inhibitor encoding function of the CDKN2A locus is principally relevant [ 26 ].…”
Section: The Role Of Cdks In Pancreatic Cancermentioning
The family of cyclin-dependent kinases (CDKs) has critical functions in cell cycle regulation and controlling of transcriptional elongation. Moreover, dysregulated CDKs have been linked to cancer initiation and progression. Pharmacological CDK inhibition has recently emerged as a novel and promising approach in cancer therapy. This idea is of particular interest to combat pancreatic ductal adenocarcinoma (PDAC), a cancer entity with a dismal prognosis which is owed mainly to PDAC’s resistance to conventional therapies. Here, we review the current knowledge of CDK biology, its role in cancer and the therapeutic potential to target CDKs as a novel treatment strategy for PDAC.
“…Furthermore, ZNF655 knockdown resulted in downregulation of CCND1 expression and inhibition of PI3K/AKT signaling pathway in pancreatic cancer cells. Additionally, the characteristics of early lesions also include the inactivation of the tumor suppressor gene CDKN2A and the overexpression of the oncogene CDKN1A, which promote the transition of the cell cycle from the G1 phase to the S phase [36]. In later lesions, two key tumor suppressor genes, Smad4 and TP53, were inactivated.…”
Pancreatic cancer has an extremely terrible prognosis and is a common cause of cancer death. In this study, the clinic value, biological function and underlying mechanisms of Zinc finger protein 655 (ZNF655) in human pancreatic cancer were evaluated. The expression level of ZNF655 in pancreatic cancer was determined by immunohistochemistry (IHC) staining. The biological effects of ZNF655 in pancreatic cancer cells was investigated by loss/gain-of-function assays in vitro and in vivo. The downstream molecular mechanism of ZNF655 was explored using co-immunoprecipitation (Co-IP), dual-luciferase reporter and chromatin immunoprecipitation (Ch-IP). ZNF655 expression was significantly elevated in human pancreatic cancer and possessed clinical value in predicting poor prognosis. Functionally, ZNF655 knockdown inhibited the biological progression of pancreatic cancer cells, which was characterized by weaken proliferation, enhanced apoptosis, arrested cell cycle in G2, impeded migration, and suppressed tumor growth. Mechanistically, ZNF655 played an important role in promoting the binding of E2F transcription factor 1 (E2F1) to the cyclin-dependent kinase 1 (CDK1) promoter. Furthermore, knockdown of CDK1 alleviated the promoting effects of ZNF655 overexpression in pancreatic cancer cells. The promotive role of ZNF655 in pancreatic cancer via CDK1 was determined, which drew further interest regarding its clinical application as a promising therapeutic target.
“…The tumor suppressor p53 is a pivotal nuclear transcription factor that is activated by various cellular stress reactions such as oxidative stress and DNA damage and accumulates in the nucleus, thereby playing an important role in regulation of cell cycle and induction of irreversible apoptosis [53]. The cyclin-dependent kinase inhibitor (CDKI) p21 is a downstream effector of p53, and its activation under oxidative stress indicates that p53-dependent cell cycle arrest is completely triggered [54]. The interaction amongst cyclins, cyclin-dependent kinases (CDK), and CDKI is involved in the regulation of cell cycle.…”
Oxidative damage to retinal pigment epithelial (RPE) has been identified as one of the major regulatory factors in the pathogenesis of age-related macular degeneration (AMD). Catalpol is an iridoid glucoside compound that has been found to possess potential antioxidant activity. In the present study, we aimed to investigate the protective effect of catalpol on RPE cells under oxidative stress and to elucidate the potential molecular mechanism involved. We found that catalpol significantly attenuated hydrogen peroxide (H2O2)-induced cytotoxicity, G0/G1 phase cell cycle arrest, and apoptosis in RPE cells. The overproduction of reactive oxygen species (ROS) and malondialdehyde (MDA) stimulated by oxidative stress and the corresponding reductions in antioxidant glutathione (GSH) and superoxide dismutase (SOD) levels were largely reversed by catalpol pretreatment. Moreover, catalpol pretreatment markedly activated the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and its downstream antioxidant enzymes, catalase (CAT), heme oxygenase-1 (HO-1), and NADPH dehydrogenase (NQO1). It also increased the expression levels of cyclin E Bcl-2, cyclin A, and cyclin-dependent kinase 2 (CDK2) and decreased the expression levels of Bax, Fas, cleaved PARP, p-p53, and p21 cleaved caspase-3, 8, and 9. The oxidative stress-induced formation of the Keap1/Nrf2 complex in the cytoplasm was significantly blocked by catalpol pretreatment. These results indicate that catalpol protected RPE cells from oxidative stress through a mechanism involving the activation of the Keap1/Nrf2/ARE pathways and the inactivation of oxidative stress-mediated pathways of apoptosis.
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