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Growth inhibition of head and neck squamous cell carcinoma cells by sgRNA targeting the cyclin D1 mRNA based on TRUE gene silencing.

Head and neck squamous cell carcinoma (HNSCC) exhibits increased expression of cyclin D1 (CCND1). Previous studies have shown a correlation between poor prognosis of HNSCC and cyclin D1 overexpression. tRNase ZL-utilizing efficacious gene silencing (TRUE gene silencing) is one of the RNA-mediated gene expression control technologies that have therapeutic potential. This technology is based on a unique enzymatic property of mammalian tRNase ZL, which is that it can cleave any target RNA at any desired site by recognizing a pre-tRNA-like complex formed between the target RNA and an artificial sm…

RSK inhibitor BI-D1870 inhibits acute myeloid leukemia cell proliferation by targeting mitotic exit.

The 90 kDa Ribosomal S6 Kinase (RSK) drives cell proliferation and survival in cancers, although its oncogenic mechanism has not been well characterized. Phosphorylated level of RSK (T573) was increased in acute myeloid leukemia (AML) patients and associated with poor survival. To examine the role of RSK in AML, we analyzed apoptosis and the cell cycle profile following treatment with BI-D1870, a potent inhibitor of RSK. BI-D1870 treatment increased the G2/M population and induced apoptosis in AML cell lines and patient AML cells. Characterization of mitotic phases showed that the metaphase/an

Role of Cyclin-Dependent Kinase Inhibitors in Endometrial Cancer.

Endometrial Cancer (EC) is an important cause of death in women worldwide. Despite early diagnosis and optimal treatment of localized disease, relapsed patients have few therapeutic options because after first line therapy, currently no standard of care exists. On the basis of endocrine positivity of most endometrioid ECs, Endocrine Therapy (ET) is a reasonable and widely accepted option. Better knowledge of molecular mechanisms involved in cancer highlighted the deregulated activity of Cyclin-Dependent Kinases (CDKs) in the cell cycle as a hallmark of carcinogenesis supporting the development

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… G1/S phase transition is controlled by Cdk4/6-cyclin D and Cdk2-cyclin E complexes. … In HR-positive BC, ER activates the promoter of CCND1, a gene encoding for cyclin D. Indeed, cyclin D is amplified or overexpressed in 20% and 50% of cases, respectively, while mutations of RB are rare [ 50 , 51 , 52 ]. …

Recent Progress in CDK4/6 Inhibitors and PROTACs.

Cell division in eukaryotes is a highly regulated process that is critical to the life of a cell. Dysregulated cell proliferation, often driven by anomalies in cell Cyclin-dependent kinase (CDK) activation, is a key pathological mechanism in cancer. Recently, selective CDK4/6 inhibitors have shown clinical success, particularly in treating advanced-stage estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. This review provides an in-depth analysis of the action mechanism and recent advancements in CDK4/6 inhibitors, categorizing them based

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… Upregulation of cyclin D and the formation of cyclin D-CDK4/6 complexes, which competitively bind CIP/KIP, leads to redistribution of CIP/KIP, thus activating cyclin E-CDK2 and promoting the G1-S transition. … Thus far, many primary resistance mechanisms have been identified, all of which seem to involve activation of the cyclin D-CDK4/6-Rb pathway [ 132 ]. …

Small compound 6-O-angeloylplenolin induces mitotic arrest and exhibits therapeutic potentials in multiple myeloma.

BackgroundMultiple myeloma (MM) is a disease of cell cycle dysregulation while cell cycle modulation can be a target for MM therapy. In this study we investigated the effects and mechanisms of action of a sesquiterpene lactone 6-O-angeloylplenolin (6-OAP) on MM cells.Methodology/principal findingsMM cells were exposed to 6-OAP and cell cycle distribution were analyzed. The role for cyclin B1 to play in 6-OAP-caused mitotic arrest was tested by specific siRNA analyses in U266 cells. MM.1S cells co-incubated with interleukin-6 (IL-6), insulin-like growth factor-I (IGF-I), or bone marrow stromal

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… Immunol Rev 194 39 47 12846806 10.1034/j.1600-065x.2003.00065.x 11 Bergsagel PL Kuehl WM 2003 Critical roles for immunoglobulin translocations and cyclin D dysregulation in multiple myeloma. …

TCF12 and LncRNA MALAT1 Cooperatively Harness High Cyclin D1 but Low β-Catenin Gene Expression to Exacerbate Colorectal Cancer Prognosis Independently of Metastasis.

Metastasis is a well-known factor worsening colorectal cancer (CRC) prognosis, but mortality mechanisms in non-metastatic patients with poor … al WNT. We investigated the impact of WNT downstream genes CTNNB1 and CCND1, encoding β-catenin and cyclin D1, respectively, on survival in CRC patients with this alliance. Tumors with higher TCF12 and MALAT1 gene expressions alongside increased β-catenin gene expressions were classified as having a "Pan-CMS-2 pattern", showing relatively better prognoses. …

A same-day assay predicts apoptotic response to combined BCL-2 and MCL-1 BH3-mimetic targeting in multiple myeloma cells.

Recent advances in treatment options for multiple myeloma (MM) have positive impact on patient survival. However, there is a short fall of rapid and reliable assays that can predict patient response to novel agents. The anti-apoptotic proteins B-cell lymphoma-2 (BCL-2) and myeloid cell leukaemia-1 (MCL-1), are necessary for MM survival, although most myelomas are more dependent on MCL-1. BCL-2 inhibition alone yields significant cytotoxicity in only a minority of cases, therefore targeting both proteins simultaneously, is a therapeutic option. Venetoclax and S63845 are BCL-2 and MCL-1 targetin

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… A signature of MM is cell cycle dysregulation characterised by over‐expression of cyclin D proteins along with reliance on anti‐apoptotic members of the BCL‐2 (B‐cell lymphoma‐2) family for survival [ 4 ]. … FIGURE 2 The combination of venetoclax and S63845 causes decreased expression of pro‐survival BCL‐2 family members and cyclin D proteins. …

Metformin Increases Survival in Hypopharyngeal Cancer Patients with Diabetes Mellitus: Retrospective Cohort Study and Cell-Based Analysis.

Hypopharyngeal squamous cell carcinoma (HSCC) is usually diagnosed at an advanced stage, leading to a poor prognosis. Even after improvement … cell-based analysis further indicated that metformin treatment regulated p38/JNK pathway to reduce Cyclin D1 and Bcl-2 expressions. In addition, metformin activated the pathways of AMPKα and MEK/ERK to phosphorylate p27(Thr198) and reduce mTOR phosphorylation in cells. These actions direct cells toward G1 cell cycle arrest, apoptosis, and autophagy. Our r …

Knockdown of lncRNA AL928768.3 inhibits multiple myeloma cell proliferation by inducing cell cycle arrest in G0/G1 phase.

BackgroundMultiple myeloma (MM) is a B-lymphocyte-derived malignancy. It ranks as the second most common hematological malignancy, with rela … blot analysis showed that knockdown of lncRNA AL significantly inhibited the expression of CDK2 and cyclin D1 and promoted the expression of cyclin suppressor p21. Knockdown of lncRNA AL significantly inhibited the proliferation of MM cells in nude mice.ConclusionsLncRNA AL was highly expressed in MM patients. Knockdown of this gene significantly inhibited …

Tumour Cell Size Control and Its Impact on Tumour Cell Function.

Cell size is an important component of cell morphological characteristics. It reflects the characteristics of the cell type, nutritional status, growth stage and physiological function. The cell size of cells of the same type tends to be homogeneous and stable. However, in tumour cells, mutations in cell cycle genes and cytoskeletal genes and overexpression of the corresponding signalling pathways often lead to large variations in tumour cell size. Tumour cells regulate cell size and growth and proliferation through multiple signalling pathways, such as PI3K/Akt/mTOR, Myc and Hippo pathways, w

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… Cyclin D is activated by the Ras‐MAPK or PI3K‐Akt pathways or by oncogenes such as Myc [ 47 , 48 ]. … Persistently activated PI3K/Akt/mTOR signalling in tumours reduces ubiquitination and degradation of Cyclin D, promotes synthesis and assembly of Cyclin D‐related proteins, and increases expression of the Cyclin D‐CDK4/6 complex [ 64 ]. …

Inhibition of Plk1 and Cyclin B1 expression results in panobinostat-induced G₂ delay and mitotic defects.

The development of clinically useful histone deacetylase inhibitors has expanded greatly. In a preclinical study, we showed that panobinostat (LBH589) inhibits cell cycle progression of human head and neck squamous cell carcinoma (HNSCC) cell lines at G₂/M and an associated decrease in expression of particular genes required for passage through G₂ and mitosis. In this study we sought to analyse the mechanistic underpinnings of panobinostat-induced growth arrest. HNSCC cell lines were synchronised and progression through mitosis monitored. We demonstrate that panobinostat causes a marked G₂ del

Temsirolimus in the treatment of relapsed and/or refractory mantle cell lymphoma.

Patients with mantle cell lymphoma (MCL) have a poor prognosis; consequently, new therapeutic approaches, such as rapamycin and its derivates, mammalian target of rapamycin (mTOR) inhibitors, are warranted. Temsirolimus (also known as CCI-779), a dihydroester of rapamycin, in MCL cell lines inhibited mTOR, downregulated p21 and v-Raf, and induced autophagy. The first clinical trial in MCL patients was performed using 250 mg of temsirolimus weekly for 6-12 cycles. The overall response rate was 38%; the median time to progression was 6.5 months, median overall survival was 12 months, and the med

Lost in transcription: molecular mechanisms that control HIV latency.

Highly active antiretroviral therapy (HAART) has limited the replication and spread of the human immunodeficiency virus (HIV). However, despite treatment, HIV infection persists in latently infected reservoirs, and once therapy is interrupted, viral replication rebounds quickly. Extensive efforts are being directed at eliminating these cell reservoirs. This feat can be achieved by reactivating latent HIV while administering drugs that prevent new rounds of infection and allow the immune system to clear the virus. However, current approaches to HIV eradication have not been effective. Moreover,

The Proliferative and Apoptotic Landscape of Basal-like Breast Cancer.

Basal-like breast cancer (BLBC) is an aggressive molecular subtype that represents up to 15% of breast cancers. It occurs in younger patients, and typically shows rapid development of locoregional and distant metastasis, resulting in a relatively high mortality rate. Its defining features are that it is positive for basal cytokeratins and, epidermal growth factor receptor and/or c-Kit. Problematically, it is typically negative for the estrogen receptor and human epidermal growth factor receptor 2 (HER2), which means that it is unsuitable for either hormone therapy or targeted HER2 therapy. As

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… The high expression of the components of the cyclin D-CDK4/6 complex and their association with poor prognosis is surprising given the canonical role of CDK4 and CDK6 in RB phosphorylation. … Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4. Genes Dev. 1993;7:331–342. doi: 10.1101/gad.7.3.331. 48. Malumbres M., Barbacid M. Mammalian cyclin-dependent kinases. Trends Biochem. …

Abemaciclib, A Selective CDK4/6 Inhibitor, Restricts the Growth of Pediatric Ependymomas.

Pediatric ependymomas are a type of malignant brain tumor that occurs in children. The overall 10-year survival rate has been reported as being 45-75%. Maximal safe surgical resection combined with adjuvant chemoradiation therapy is associated with the highest overall and progression-free survival rates. Despite aggressive treatment, one-third of ependymomas exhibit recurrence within 2 years of initial treatment. Therefore, this study aimed to find new agents to overcome chemoresistance and defer radiotherapy treatment since, in addition, radiation exposure may cause long-term side effects in

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… Cyclin D as a therapeutic target in cancer Nat. Rev. Cancer 2011 11 558 572 10.1038/nrc3090 21734724 11. Santarius T. Shipley J. Brewer D. Stratton M.R. Cooper C.S. A census of amplified and overexpressed human cancer genes Nat. Rev. Cancer 2010 10 59 64 10.1038/nrc2771 20029424 12. Pernas S. …

Recent advances in development of CDK7 inhibitors and their clinical trials: a narrative review.

Background and objectiveCDK7, a member of the CDK-activating kinase (CAK) family, plays a key role in cell cycle, transcriptional regulation and in regulating the proliferation and apoptosis of tumor cells. Some evidence suggests that CDK7 is a promising target for cancer treatments, so it is of great significance to develop an efficient and highly selective CDK7 inhibitor. CDK7 inhibitors have not yet been marketed. This review focuses on some selective CDK7 inhibitors currently in clinical research, and introduces their targets, indications, and the latest clinical trial progress in detail.M

Identification of the sAPRIL binding peptide and its growth inhibition effects in the colorectal cancer cells.

BackgroundA proliferation-inducing ligand (APRIL) is a member of the tumor necrosis factor (TNF) super family. It binds to its specific receptors and is involved in multiple processes during tumorigenesis and tumor cells proliferation. High levels of APRIL expression are closely correlated to the growth, metastasis, and 5-FU drug resistance of colorectal cancer. The aim of this study was to identify a specific APRIL binding peptide (BP) able to block APRIL activity that could be used as a potential treatment for colorectal cancer.MethodsA phage display library was used to identify peptides tha

Iron deprivation in cancer--potential therapeutic implications.

Iron is essential for normal cellular function. It participates in a wide variety of cellular processes, including cellular respiration, DNA synthesis, and macromolecule biosynthesis. Iron is required for cell growth and proliferation, and changes in intracellular iron availability can have significant effects on cell cycle regulation, cellular metabolism, and cell division. Perhaps not surprisingly then, neoplastic cells have been found to have higher iron requirements than normal, non-malignant cells. Iron depletion through chelation has been explored as a possible therapeutic intervention i

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… The cyclin most consistently and dramatically inhibited by iron chelation is cyclin D [ 44 , 45 , 46 ]. Cyclin D forms a complex with cdk4 or cdk6 during G1 to promote expression of the cyclin E–cdk2 complex and hyperphosphorylation of Rb [ 43 ]. … Iron chelation appears to cause ubiquitin-independent proteasomal degradation of Cyclin D, in a manner similar to the effect on p21 CIP1/WAF1 [ 46 ]. …

Arctiin Inhibits Inflammation, Fibrosis, and Tumor Cell Migration in Rats With Ehrlich Solid Carcinoma.

Background and objectivesESC or Ehrlich solid carcinoma is a type of tumor originating from a spontaneous mammary adenocarcinoma in mice. It … transcription 3 (STAT3), transforming growth factor (TGF)-β, endothelial growth factor (VEGF), and cyclin D1 were assessed in another part of the muscle samples.ResultsWhen ESC rats were given arctiin as a treatment, their mean survival time increased and their tumor volume and weight decreased. Additionally, when tumor tissue was examined under an electr …

Translational Advances in Oncogene and Tumor-Suppressor Gene Research.

Cancer, characterized by the uncontrolled proliferation of cells, is one of the leading causes of death globally, with approximately one in five people developing the disease in their lifetime. While many driver genes were identified decades ago, and most cancers can be classified based on morphology and progression, there is still a significant gap in knowledge about genetic aberrations and nuclear DNA damage. The study of two critical groups of genes-tumor suppressors, which inhibit proliferation and promote apoptosis, and oncogenes, which regulate proliferation and survival-can help to unde

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… CDK4/CDK6-cyclin D complexes help push the cell past the restriction point in G 1 , committing to a new division cycle ( Figure 1 ) [ 34 ]. … Cyclin D-Cdk4,6 Drives Cell-Cycle Progression via the Retinoblastoma Protein’s C-Terminal Helix Mol. Cell 2019 74 758 770.e4 10.1016/j.molcel.2019.03.020 30982746 PMC6800134 35. Pavletich N.P. …