Cancer is characterized by abnormal cell proliferation. Cyclins and cyclin-dependent kinases (CDKs) have been recognized as essential regulators of the intricate cell cycle, orchestrating DNA replication and transcription, RNA splicing, and protein synthesis. Dysregulation of the CDK pathway is prevalent in the development and progression of human cancers, rendering cyclins and CDKs attractive therapeutic targets. Several CDK4/6 inhibitors have demonstrated promising anti-cancer efficacy and have been successfully translated into clinical use, fueling the development of CDK-targeted therapies. With this enthusiasm for finding novel CDK-targeting anti-cancer agents, there have also been exciting advances in the field of targeted protein degradation through innovative strategies, such as using proteolysis-targeting chimera, heat shock protein 90 (HSP90)‍-mediated targeting chimera, hydrophobic tag-based protein degradation, and molecular glue. With a focus on the translational potential of cyclin- and CDK-targeting strategies in cancer, this review presents the fundamental roles of cyclins and CDKs in cancer. Furthermore, it summarizes current strategies for the proteasome-dependent targeted degradation of cyclins and CDKs, detailing the underlying mechanisms of action for each approach. A comprehensive overview of the structure and activity of existing CDK degraders is also provided. By examining the structure‍‒‍activity relationships, target profiles, and biological effects of reported cyclin/CDK degraders, this review provides a valuable reference for both CDK pathway-targeted biomedical research and cancer therapeutics.
Humans ; Neoplasms/metabolism* ; Cyclin-Dependent Kinases/antagonists & inhibitors* ; Cyclins/metabolism* ; Proteolysis ; Antineoplastic Agents/pharmacology* ; Molecular Targeted Therapy ; Proteasome Endopeptidase Complex/metabolism* ; Animals

OBJECTIVES: To investigate the structural changes of rat thoracic aorta and changes in expression levels of Bmal1 and cyclins in thoracic aorta endothelial cells following heat stress. METHODS: Twenty male SD rats were randomized equally into control group and heat stress group. After exposure to 32 ℃ for 2 weeks in the latter group, the rats were examined for histopathological changes and Bmal1 expression in the thoracic aorta using HE staining and immunohistochemistry. In the cell experiments, cultured rat thoracic aortic endothelial cells (RTAECs) were incubated at 40 ℃ for 12 h with or without prior transfection with a Bmal1-specific small interfering RNA (si-Bmal1) or a negative sequence. In both rat thoracic aorta and RTAECs, the expressions of Bmal1, the cell cycle proteins CDK1, CDK4, CDK6, and cyclin B1, and apoptosis-related proteins Bax and Bcl-2 were detected using Western blotting. TUNEL staining was used to detect cell apoptosis in rat thoracic aorta, and the changes in cell cycle distribution and apoptosis in RTAECs were analyzed with flow cytometry. RESULTS: Compared with the control rats, the rats exposed to heat stress showed significantly increased blood pressures and lowered heart rate with elastic fiber disruption and increased expressions of Bmal1, cyclin B1 and CDK1 in the thoracic aorta (P<0.05). In cultured RTAECs, heat stress caused significant increase of Bmal1, cyclin B1 and CDK1 protein expression levels, which were obviously lowered in cells with prior si-Bmal1 transfection. Bmal1 knockdown also inhibited heat stress-induced increase of apoptosis in RTAECs as evidenced by decreased expression of Bax and increased expression of Bcl-2. CONCLUSIONS Heat stress upregulates Bmal1 expression and causes alterations in expressions of cyclins to trigger apoptosis of rat thoracic aorta endothelial cells, which can be partly alleviated by suppressing Bmal1 expression.
Animals ; ARNTL Transcription Factors/genetics* ; Male ; Aorta, Thoracic/metabolism* ; Rats ; Rats, Sprague-Dawley ; Endothelial Cells/metabolism* ; Apoptosis ; Cells, Cultured ; Heat-Shock Response ; Cyclin B1/metabolism* ; CDC2 Protein Kinase/metabolism* ; Cyclins/metabolism* ; RNA, Small Interfering ; bcl-2-Associated X Protein/metabolism*

The cell cycle is a complex process that involves DNA replication, protein expression, and cell division. Dysregulation of the cell cycle is associated with various diseases. Cyclin-dependent kinases (CDKs) and their corresponding cyclins are major proteins that regulate the cell cycle. In contrast to inhibition, a new approach called proteolysis-targeting chimeras (PROTACs) and molecular glues can eliminate both enzymatic and scaffold functions of CDKs and cyclins, achieving targeted degradation. The field of PROTACs and molecular glues has developed rapidly in recent years. In this article, we aim to summarize the latest developments of CDKs and cyclin protein degraders. The selectivity, application, validation and the current state of each CDK degrader will be overviewed. Additionally, possible methods are discussed for the development of degraders for CDK members that still lack them. Overall, this article provides a comprehensive summary of the latest advancements in CDK and cyclin protein degraders, which will be helpful for researchers working on this topic.
Humans ; Cell Cycle/physiology* ; Cell Division ; Cyclin-Dependent Kinases/metabolism* ; Cyclins/metabolism*

Cell cycle plays a crucial role in cell development. Cell cycle progression is mainly regulated by cyclin dependent kinase (CDK), cyclin and endogenous CDK inhibitor (CKI). Among these, CDK is the main cell cycle regulator, binding to cyclin to form the cyclin-CDK complex, which phosphorylates hundreds of substrates and regulates interphase and mitotic progression. Abnormal activity of various cell cycle proteins can cause uncontrolled proliferation of cancer cells, which leads to cancer development. Therefore, understanding the changes in CDK activity, cyclin-CDK assembly and the role of CDK inhibitors will help to understand the underlying regulatory processes in cell cycle progression, as well as provide a basis for the treatment of cancer and disease and the development of CDK inhibitor-based therapeutic agents. This review focuses on the key events of CDK activation or inactivation, and summarizes the regulatory processes of cyclin-CDK at specific times and locations, as well as the progress of research on relevant CDK inhibitor therapeutics in cancer and disease. The review concludes with a brief description of the current challenges of the cell cycle process, with the aim to provide scientific references and new ideas for further research on cell cycle process.
Cyclin-Dependent Kinases/metabolism* ; Cyclins/metabolism* ; Protein Serine-Threonine Kinases ; Cell Cycle Proteins/metabolism* ; Cell Cycle/physiology* ; Cyclin-Dependent Kinase 2

Tannic acid (TA) is a water-soluble polyphenol compound found in various herbal plants. We investigated the chemopreventive effects of TA on FaDu hypopharyngeal squamous carcinoma cells. In an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, TA showed dose-dependent cytotoxicity with a half maximal inhibitory concentration (IC50) of 50 µM. Cell cycle analysis and immunofluorescence imaging demonstrated that under low-dose (25 µM) treatment, FaDu cells were arrested in G2/M phase, and as the dose of TA was increased, apoptosis was induced with the increase of cell population at sub-G1 phase. The expressions of various cyclins, including cyclin D1 and cyclin-dependent kinases (CDK-1 and CDK-2), were down-regulated at low doses of TA, whereas apoptotic effectors such as cleaved caspase 3, cleaved caspase 7, and poly (ADP-ribose) polymerase (PARP) were expressed in a dose-dependent manner in Western blotting. In addition, TA-induced apoptosis of FaDu cells might be mediated by the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase pathway, with the upregulation of p-AKT/p-PKB (phosphorylated protein kinase B) and p-ERK. Overall, our data support the hypothesis that TA is a potential candidate agent for the treatment of hypopharyngeal cancer.
Apoptosis ; Blotting, Western ; Carcinoma, Squamous Cell ; Caspase 3 ; Caspase 7 ; Cell Cycle ; Cyclin D1 ; Cyclin-Dependent Kinases ; Cyclins ; Epithelial Cells ; Fluorescent Antibody Technique ; Hypopharyngeal Neoplasms ; Phosphotransferases ; Protein Kinases ; Tannins ; Up-Regulation

BACKGROUND: Helicobacter pylori infection is a major risk factor in the development of gastric cancer. H. pylori infection of gastric epithelial cells increases the levels of reactive oxygen species (ROS), activates oncogenes, and leads to β-catenin-mediated hyper-proliferation. β-Carotene reduces ROS levels, inhibits oxidant-mediated activation of inflammatory signaling and exhibits anticancer properties. The present study was carried out to determine if β-carotene inhibits H. pylori-induced cell proliferation and the expression of oncogenes c-myc and cyclin E by reducing the levels of β-catenin and phosphorylated glycogen synthase kinase 3β (p-GSK3β). METHODS: Gastric epithelial AGS cells were pre-treated with β-carotene (5 and 10 μM) for 2 hours prior to H. pylori infection and cultured for 6 hours (for determination of the levels of p-GSK3β, GSK3β, and β-catenin) and 24 hours (for determination of cell viability and protein levels of c-myc and cyclin E). Cell viability was determined by the MTT assay and protein levels were determined via western blot-based analysis. RESULTS: β-Carotene inhibited H. pylori-induced increases in the percentage of viable cells, phosphorylated GSK3β (p-GSK3β), and the levels of β-catenin, c-myc and cyclin E. CONCLUSIONS: β-Carotene inhibits H. pylori-induced hyper-proliferation of gastric epithelial cells by suppressing β-catenin signaling and oncogene expression.
beta Carotene ; beta Catenin ; Cell Proliferation ; Cell Survival ; Cyclin E ; Cyclins ; Epithelial Cells ; Glycogen Synthase Kinases ; Helicobacter pylori ; Helicobacter ; Oncogenes ; Reactive Oxygen Species ; Risk Factors ; Stomach Neoplasms

After FDA approval of cetuximab at 2006, receptor tyrosine kinase, including an epidermal growth factor receptor, blocking agents have been evaluated for head and neck squamous cell carcinoma (HNSCC). Agents targeting PI3K/Akt/mTOR, IL-6/JAK/STAT3, vascular endothelial growth factor receptor, and cyclin D-CDK-4/6-INK4/Rb pathway have developed. Most of them have failed to demonstrate better treatment outcome in recurrent and/or metastatic (R/M) HNSCC than conventional chemotherapy. Since a pivotal role of PD-1/PD-L1 pathway in immunological tumor microenvironment was revealed, the immune checkpoint inhibitors, including pembrolizumab and nivolumab, have opened new paradigm of cancer treatment modality and propagates other immune-based therapies for R/M HNSCC. Various types of combination trials consisting of immunotherapy with other class of immunotherapy, targeted agents, radiation therapy, or conventional chemotherapy have been under investigation to improve treatment outcome. Biomarker studies to find an optimal candidate for the newly developed agents are accompanied. These clinical trials lead to tailored approach based on immunotherapy with precision medicine is expected to lead to promising results.
Carcinoma, Squamous Cell ; Cetuximab ; Cyclins ; Drug Therapy ; Epithelial Cells ; Head ; Immunotherapy ; Molecular Targeted Therapy ; Neck ; Precision Medicine ; Protein-Tyrosine Kinases ; Receptor, Epidermal Growth Factor ; Receptors, Vascular Endothelial Growth Factor ; Treatment Outcome ; Tumor Microenvironment

PURPOSE: This study was conducted to verify the induction and mechanism of selective apoptosis in G361 melanoma cells using anti-HER2 antibody-conjugated gold nanoparticles (GNP-HER2). MATERIALS AND METHODS: Following GNP-HER2 treatment of G361 cells, cell cycle arrest and apoptosis were measured by WST-1 assay, Hemacolor staining, Hoechst staining, immunofluorescence staining, fluorescence-activated cell sorting analysis, and Western blotting.
Actins ; Apoptosis Inducing Factor ; Apoptosis ; Blotting, Western ; Caspase 3 ; Caspases ; Cell Adhesion ; Cell Cycle ; Cell Cycle Checkpoints ; Cell Death ; Cyclin A ; Cyclin D1 ; Cyclin E ; Cyclins ; Cytochromes c ; Cytoplasm ; DNA Fragmentation ; Down-Regulation ; Flow Cytometry ; Fluorescent Antibody Technique ; Focal Adhesions ; Melanoma ; Mitochondria ; Nanoparticles ; Phosphotransferases ; Receptor, Epidermal Growth Factor ; Up-Regulation

PURPOSE: To determine the possible effects of chronic exposure of low dose benzalkonium chloride (BAK) on trabecular meshwork cells, and to characterize the pathways involved in the effects. METHODS: Trabecular meshwork cells were treated with 0.0005%, 0.00075%, 0.001%, and 0.0025% BAK for 10 minutes; then, the cells were transferred to a new medium for 24 hours. This process was repeated three times. Cell survival was assessed using the MTT assay to determine the non-apoptotic BAK concentration. Senescence-associated (SA)-β-gal staining was performed to compare quantitatively the cellular senescence of BAK-treated cells with the control group. Cells treated with BAK were analyzed by western blot to determine whether the expressions of cell cycle regulators were affected. RESULTS: Two concentrations (0.0005% and 0.00075%) showed persistent cell viability and were chosen for further experiments. After SA-β-gal staining, cells treated with 0.0005% and 0.00075% BAK showed 28% (± 2.08), 37% (± 2.08) increases in cellular senescence expression, respectively, when compared with control cells (p < 0.05). To identify the molecular pathways involved in cell cycle arrest via BAK, western blot analysis was performed on trabecular meshwork cells, resulting in decreased expressions of cyclin E/CDK2, and increased expressions of the upper stream control molecules, p53 and p21. CONCLUSIONS: Chronic exposure to low dose BAK accelerated cell senescence through cell cycle arrest. Because senescent cells of the trabecular meshwork can inhibit its outflow pathway function and ultimately worsen the glaucomatous process, long-term usage of topical glaucoma medications containing BAK should be conducted with caution.
Aging ; Benzalkonium Compounds ; Blotting, Western ; Cell Aging ; Cell Cycle ; Cell Cycle Checkpoints ; Cell Survival ; Cyclins ; Glaucoma ; Rivers ; Trabecular Meshwork

BACKGROUND: 15,16-dihydrotanshinone I (DHTS) is a natural abietane diterpenoid that is mainly found in the roots of Salvia miltiorrhiza Bunge (Labiatae). DHTS exhibits a potential anti-proliferative effect in various human cancer cells. However, the mechanisms of action of DHTS as an anti-cancer agent have not been fully elucidated. Therefore, the present study investigated the anti-cancer effect of DHTS in terms of cell cycle regulation and the regulation of the AMP-activated protein kinase (AMPK)/Akt/mTOR signaling pathway in SK-HEP-1 human hepatocellular carcinoma cells. METHODS: The anti-proliferative effects of DHTS were evaluated by the sulforhodamine B assay in SK-HEP-1 cells. Cell cycle distribution was analyzed by flow cytometry. The elucidation of mechanisms of action such as the AMPK/AKT/mTOR and mitogen-activated protein kinase (MAPK) pathway was assessed by Western blot analysis. RESULTS: DHTS showed a significant anti-proliferative activity against SK-HEP-1 cells. DHTS induced cell cycle arrest in the G0/G1 phase, which was mediated by downregulation of cyclin D1, cyclin A, cyclin E, CDK4, CDK2, c-Myc and p-Rb expression and with increased expression of the CDK inhibitor p21. DHTS also activated the AMPK signaling. In addition, DHTS downregulated the Akt/mTOR and MAPK signaling pathways. CONCLUSIONS: Our results suggest that the anti-proliferative activity of DHTS might be associated with the induction of G0/G1 phase cell cycle arrest and regulation of AMPK/Akt/mTOR and MAPK signaling pathways in SK-HEP-1 cells.
AMP-Activated Protein Kinases ; Blotting, Western ; Carcinoma, Hepatocellular ; Cell Cycle Checkpoints ; Cell Cycle ; Cyclin A ; Cyclin D1 ; Cyclin E ; Cyclins ; Down-Regulation ; Flow Cytometry ; Humans ; Protein Kinases ; Salvia miltiorrhiza