Cell Mitosis Research Articles

Combination Effects of Integrin-linked Kinase and Abelson Kinase Inhibition on Aberrant Mitosis and Cell Death in Glioblastoma Cells.

In cancer cells, inhibition of integrin-linked kinase (ILK) increases centrosome declustering causing mitotic arrest and cell death. Yet, not all cancer cells are susceptible to anti-ILK treatment alone. We investigate a combination drug strategy targeting ILK and another oncogenic kinase, Abelson kinase (ABL). Drug-concentration viability assays (i.e., MTT assays) indicate that ILK and ABL inhibitors in combination decreased the viability of glioblastoma cells over the ILK drug QLT-0267 alone. Combination strategies also increased aberrant mitoses and cell death over QLT-0267 alone. This was evident from an increase in mitotic arrest, apoptosis and a sub-G1 peak following FAC analysis. In vitro, ILK and ABL localized to the centrosome and the putative ILK kinase domain was important for this localization. Increased levels of cytosolic ABL are associated with its transformative abilities. ILK inhibitor effects on survival correlated with its ability to decrease cytosolic ABL levels and inhibit ABL's localization to mitotic centrosomes in glioblastoma cells. ILK inhibitor effects on ABL's centrosomal localization were reversed by the proteasomal inhibitor MG132 (a drug that inhibits ABL degradation). These results indicate that ILK regulates ABL at mitotic centrosomes and that combination treatments targeting ILK and ABL are more effective then QLT-0267 alone at decreasing the survival of dividing glioblastoma cells.

Enzyme-triggered transcytosis of drug carrier system for deep penetration into hepatoma tumors

In recent years, nano-drug delivery systems have made considerable progress in the direction of tumor treatment, but the low permeability of drugs has restricted the development of nano drugs. To solve this problem, we constructed a nano-drug delivery system with the dual effects of γ-glutamyltransferase (GGT) reaction and high nuclear targeting in tumor microenvironment to promote the deep penetration of drugs. Over-expression of GGT in tumor cells can specifically recognize γ-glutamyl substrate and release amino group from the hydrolysis reaction, which makes the whole system change from negative or neutral to positive charge system. The conjugated complex with positive charge rapidly endocytosis through electrostatic interaction, enhancing its permeability in tumor parenchyma. At the same time, the cell penetrating TAT contains a large amount of lysine, which can be identified by the nuclear pore complexes (NPCs) on the surface of the nuclear membrane, showing excellent nuclear localization function. The active DOX is released in the nucleus, which inhibits the mitosis of cancer cells and enhances the active transport ability of drugs in tumor cells. Therefore, this drug delivery system actively transports adriamycin into the tumor to achieve deep penetration of drugs through enzyme response and nuclear targeting, showing high anti-tumor activity and can be effectively applied to the treatment of liver cancer.

Crosstalk between Microtubule Stabilizing Agents and Prostate Cancer.

A variety of microtubule-stabilizing cytotoxic agents (MSA) with diverse chemical scaffolds have been discovered from marine sponges, microorganisms, and plants. Two MSAs, docetaxel and cabazitaxel, are the exclusive chemotherapeutics that convey a survival benefit in patients with castration-resistant prostate cancer (CRPC). Additional MSAs have been investigated for their potential in treating prostate cancer in both clinical and preclinical settings. Independent of promoting mitotic arrest, MSAs can suppress the nuclear accumulation of androgen receptor (AR), which is the driving force for prostate cancer cell growth and progression. The alternative mechanism not only helps to better understand the clinical efficacy of docetaxel and cabazitaxel for AR-driven CRPC but also provides an avenue to seek better treatments for various forms of prostate cancer. The dual mechanisms of action enable MSAs to suppress AR-null prostate cancer cell proliferation by cell mitosis pathway and to interfere with the AR signaling pathway in AR positive cells. MSA chemotherapeutics, being administered alone or in combination with other therapeutics, may serve as the optimal therapeutic option for patients with either castration-sensitive or castration-resistant prostate cancer. This review provides an overview of the anti-prostate cancer profiles (including preclinical and clinical studies, and clinical use) of diverse MSAs, as well as the mechanism of action.

NADPH increase in mitosis in aneuploid tumour cells protects against genomic aberrations.

NADPH increase in mitosis in aneuploid tumour cells protects against genomic aberrations.

Discovery of a New Chalcone-Trimethoxycinnamide Hybrid with Antimitotic Effect: Design, Synthesis, and Structure-Activity Relationship Studies.

In this work, the design and synthesis of a new chalcone-trimethoxycinnamide hybrid (7) based on the combination of subunits of two promising antiproliferative compounds (CM-M345 (1) and BP-M345 (2)), previously obtained by our research group, are reported. In order to expand the structure-activity relationship (SAR) knowledge, a new series of 7-analogues was also designed and synthetized. All the compounds were evaluated for their antitumor activity against melanoma (A375-C5), breast adenocarcinoma (MCF-7), and colorectal carcinoma (HCT116) cell lines, as well as non-tumor HPAEpiC cells. Three of the newly synthesized compounds (6, 7, and 13) exhibited potent antiproliferative activity, mainly on colorectal tumor cells (GI50 = 2.66-3.26 μM), showing hybrid 7 selectivity for tumor cells. We performed molecular mechanism studies to evaluate the potential interference of compounds with the p53 pathway, namely, p53-MDM2 interaction and mitosis in HCT116 cells. The antiproliferative activities of compounds were shown to be p53-independent. Compound 7 emerged as an antimitotic agent by inducing the mitotic arrest of colorectal tumor cells, and subsequently, cell death.

Current progress in growth factors and extracellular vesicles in tendon healing.

Tendon injury healing is a complex process that involves the participation of a significant number of molecules and cells, including growth factors molecules in a key role. Numerous studies have demonstrated the function of growth factors in tendon healing, and the recent emergence of EV has also provided a new visual field for promoting tendon healing. This review examines the tendon structure, growth, and development, as well as the physiological process of its healing after injury. The review assesses the role of six substances in tendon healing: insulin-like growth factor-I (IGF-I), transforming growth factor β (TGFβ), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), and EV. Different growth factors are active at various stages of healing and exhibit separate physiological activities. IGF-1 is expressed immediately after injury and stimulates the mitosis of various cells while suppressing the response to inflammation. VEGF, which is also active immediately after injury, accelerates local metabolism by promoting vascular network formation and positively impacts the activities of other growth factors. However, VEGF's protracted action could be harmful to tendon healing. PDGF, the earliest discovered cytokine to influence tendon healing, has a powerful cell chemotaxis and promotes cell proliferation, but it can equally accelerate the response to inflammation and relieve local adhesions. Also useful for relieving tendon adhesion is TGF- β, which is active almost during the entire phase of tendon healing. As a powerful active substance, in addition to its participation in the field of cardiovascular and cerebrovascular vessels, tumour and chronic wounds, TGF- β reportedly plays a role in promoting cell proliferation, activating growth factors, and inhibiting inflammatory response during tendon healing.

Mitotic defects lead to unreduced sperm formation in cdk1−/− mutants

Unreduced gametes, that are important for species evolution and agricultural development, are generally believed to be formed by meiotic defects. However, we found that male diploid loach (Misgurnus anguillicaudatus) could produce not only haploid sperms, but also unreduced sperms, after cyclin-dependent kinase 1 gene (cdk1, one of the most important kinases in regulating cell mitosis) deletion. Observations on synaptonemal complexes of spermatocyte in prophase of meiosis and spermatogonia suggested that the number of chromosomes in some spermatogonia of cdk1−/− loach doubled, leading to unreduced diploid sperm production. Then, transcriptome analysis revealed aberrant expressions of some cell cycle-related genes (such as ppp1c and gadd45) in spermatogonia of cdk1−/− loach relative to wild-type loach. An in vitro and in vivo experiment further validated that Cdk1 deletion in diploid loach resulted in mitotic defects, leading to unreduced diploid sperm formation. In addition, we found that cdk1−/− zebrafish could also produce unreduced diploid sperms. This study provides important information on revealing the molecular mechanisms behind unreduced gamete formation through mitotic defects, and lays the foundation for a novel strategy for fish polyploidy creation by using cdk1 mutants to produce unreduced sperms, which can then be used to obtain polyploidy, proposed to benefit aquaculture.

Altered expression of necroptotic, angiogenic and spermatogenic proteins in degenerate testes from aged stallions

We utilized RNA sequencing to compare the testis transcriptomes of fertile, adult stallions to those of adult stallions with age-related testicular degeneration (TD). Large-scale gene ontology analysis identified pathway-wide upregulation of inflammation and alterations in apoptotic pathways that likely play roles in the disease process (Woodward et al., Eq Vet J. 2022; 1-14). In humans and mice, inflammation, together with necroptosis, and alterations in capillary density, all contribute to age-related degenerative changes (Li et. al, ELife. 2017; 6:e27692 DOI: 10.7554/eLife.27692; Das et al, Cell. 2018;(173)74-89). One objective of the current study was to identify differentially expressed genes (DEGs) that may contribute similarly to TD in the horse. We also searched for DEGs that play roles in spermatogenesis. A second objective was to use immunohistochemistry (IHC) to determine if the protein products of these genes are differentially expressed between normal and diseased testes and to determine their patterns of expression. The hypothesis is that aberrations in necroptotic, angiogenic, and spermatogenic signaling pathways contribute to the pathophysiology of TD in stallions. RNA isolation and sequencing were performed on testicular tissue samples from 3 fertile adult stallions and from 3 adult stallions with confirmed TD as previously described (Woodward et al., Eq Vet J. 2022; 1-14). Transcript expression was compared between the 2 populations using either EdgeA or DESeq2, and a minimum of >1.5x fold change and Padj<0.05 asthe cutoffs for significance. Protein expression from selected DEGs was compared between normal adult and TD tissue using IHC. In degenerate testes, significant increases in gene expression were found in testicular-origin growth factors (BMP4 (9x increase), FGF2 (9x increase), and CSF1 (7x increase)). IHC confirmed increased expression of BMP4 and FGF2 proteins in germ cells from degenerate testes. Expression of CSF1R protein also was altered, with loss of expression of the protein in early germ cells, and increased expression in later stages of spermatogenesis. Upregulation of RIPK3 (3x increase) and VEGF (17x increase) transcripts also were confirmed in degenerate testes. These genes are central to necroptotic and angiogenic pathways, respectively. IHC confirmed diffuse upregulation of the RIPK3 protein in germ cells from degenerate testes. IHC for the VEGF protein is pending. In conclusion, alterations in expression of proteins responsible for stimulation of mitosis and meiosis in male germ cells were identified. Additionally, we provide evidence that chronic inflammation, necroptosis and aberrant angiogenesis may cause age-related degenerative changes in equine testes. In mice, inhibitors of the RIPK3 pathway and stimulation of angiogenesis can ameliorate clinical signs of aging in testes and muscle respectively (Li et. al, ELife. 2017; Das et al, Cell. 2018). Financial support: Grayson Jockey Club Research Foundation.

Mitotic bookmarking by SWI/SNF subunits.

For cells to initiate and sustain a differentiated state, it is necessary that a 'memory' of this state is transmitted through mitosis to the daughter cells1-3. Mammalian switch/sucrose non-fermentable (SWI/SNF) complexes (also known as Brg1/Brg-associated factors, or BAF) control cell identity by modulating chromatin architecture to regulate gene expression4-7, but whether they participate in cell fate memory is unclear. Here we provide evidence that subunits of SWI/SNF act as mitotic bookmarks to safeguard cell identity during cell division. The SWI/SNF core subunits SMARCE1 and SMARCB1 are displaced from enhancers but are bound to promoters during mitosis, and we show that this binding is required for appropriate reactivation of bound genes after mitotic exit. Ablation of SMARCE1 during a single mitosis in mouse embryonic stem cells is sufficient to disrupt gene expression, impair the occupancy of several established bookmarks at a subset of their targets and cause aberrant neural differentiation. Thus, SWI/SNF subunit SMARCE1 has a mitotic bookmarking role and is essential for heritable epigenetic fidelity during transcriptional reprogramming.

RNAi Analysis of Potential Functions of Cyclin B3 in Reproduction of Male Oriental River Prawns (Macrobrachium nipponense).

Cyclin B3 (CycB3) is involved in the metabolic pathway of the cell cycle, playing essential roles in the regulation of cell proliferation and mitosis. CycB3 is also predicted to be involved in the reproduction of male oriental river prawns (Macrobrachium nipponense). In this study, the potential functions of CycB3 in M. nipponense were investigated using quantitative real-time PCR, RNA interference, and histological observations. The full-length DNA sequence of CycB3 in M. nipponense was 2147 base pairs (bp) long. An open reading frame of 1500 bp was found, encoding 499 amino acids. A highly conserved destruction box and two conserved cyclin motifs were found in the protein sequence of Mn-CycB3. Phylogenetic tree analysis revealed that this protein sequence was evolutionarily close to that of CycB3s of crustacean species. Quantitative real-time PCR analysis results suggested that CycB3 was involved in the process of spermiogenesis, oogenesis, and embryogenesis in M. nipponense. RNA interference analysis showed that CycB3 had a positive regulatory relationship with insulin-like androgenic gland hormone (IAG) in M. nipponense. In addition, sperm were rarely observed in the testis of double-stranded CycB3-injected prawns after 14 days of treatment, and sperm abundance was dramatically lower than that in the double-stranded GFP-injected prawns on the same day. This result indicated that CycB3 can regulate the testis reproduction in M. nipponense through inhibiting the IAG expressions. Overall, these results indicated that CycB3 plays essential roles in the regulation of male reproduction in M. nipponense, which may promote the studies of male reproduction in other crustacean species.

Evaluation of mutagenic susceptibility of different stages in germ cell development of Caenorhabditis elegans using whole genome sequencing.

In contrast to somatic mutations, mutations in germ cells affect every cell of any organism derived from the germ cell and therefore are related to numerous genetic diseases. However, there is no suitable assay to evaluate the mutagenic sensitivities of both male and female germ cells. The main type of Caenorhabditis elegans (C. elegans) is hermaphroditic, where spermatogenesis and oogenesis occur chronologically at specific stages, allowing induction of mutations in either sperm or eggs exclusively. In this study, we used the alkylating agent ethyl methanesulfonate and N-ethyl-N-nitrosourea to induce germline mutations in C. elegans at different developmental stages and analyzed mutation frequency and mutational spectrum from data gathered using next-generation sequencing (NGS) technology. Our results revealed low spontaneous mutation rates of C. elegans, along with distinct mutagenic effects elicited by the two mutagens. Our data show that the parental worms treated during germ cell mitosis, spermatogenesis, and oogenesis resulted in different mutation frequencies in their offspring, and female germ cells could be very susceptible to mutagen exposure during oogenesis. In summary, our study indicates that the use of C. elegans and its specific chronological hermaphroditism would be a promising way to explore the sensitivities of both male and female germ cells to mutagens.

Potential toxicity assessment of mycotoxin fusaric acid with the spectral shift profile on DNA.

In this study, the multiple toxicities induced by three different doses (1, 5, and 10 μM) of fusaric acid (FA), a mycotoxin, was investigated with Allium test. Physiological (percent germination, root number, root length, and weight gain), cytogenetic (micronucleus = MN, chromosomal abnormalities = CAs, and mitotic index = MI), biochemical (proline level, malondialdehyde = MDA level, catalase = CAT activity, and superoxide dismutase = SOD activity), and anatomical parameters were used as indicators of toxicity. Allium cepa L. bulbs were divided into four groups as one control and three applications. The bulbs in the control group were germinated with tap water for 7 days, and the bulbs in the treatment groups were germinated with three different doses of FA for 7 days. As a result, FA exposure caused a decrease in all physiological parameters examined at all three doses. Besides, all FA doses caused a decrease in MI and an increase in the frequency of MN and the number of CAs. FA promoted CAs such as nucleus with vacuoles, nucleus buds, irregular mitosis, bridge, and misdirection in root meristem cells. DNA and FA interactions, which are the possible causes of genotoxic effects, were examined by spectral analysis, and FA could interact with DNA through intercalation, causing bathochromic and hypochromic shifts in the spectrum. FA also causes toxicity by inducing oxidative stress in cells, confirming this; dose-related increases in root MDA and proline levels were measured as a result of FA exposure. In the root SOD and CAT enzyme activities, increases up to 5 μM doses and decreases at 10 μM doses were measured. FA exposure induced anatomical damage such as necrosis, epidermis cell damage, flattened cell nucleus, thickening of the cortex cell wall, and unclear vascular tissue in root tip meristem cells. As a result, FA caused a comprehensive toxicity by showing an inhibitory effect in A. cepa test material, and the Allium test was a very useful test in determining this toxicity.

Targeting Pokemon is a novel strategy to suppress cancer aggressiveness of non-small cell lung cancer: Identification of Pokemon as ideal target for developing anti-NSCLC drugs

Although it is widely reported that Pokemon acts as an oncogene in the pathogenesis of multiple cancers, but its role and detailed molecular mechanisms in regulating non-small cell lung cancer (NSCLC) progression have not been fully delineated. Here, by performing Real-Time qPCR analysis, we verified that Pokemon was high-expressed in NSCLC tissues and cells, compared to the corresponding normal lung tissues and epithelial cells. Then, the small interfering RNA (siRNA) for Pokemon was transfected into the NSCLC cells to verify its biological functions, and our results suggested that silencing of Pokemon suppressed the malignant phenotypes, including cell viability, mitosis, colony formation, epithelial-mesenchymal transition (EMT), mobility and cancer stem cell (CSC) properties in NSCLC cells. Mechanistically, we confirmed that knockdown of Pokemon decreased the expression levels of phosphorylated Akt (p-Akt), phosphorylated GSK-3β (p-GSK-3β) and Snail to inactivate the oncogenic Akt/GSK-3β/Snail signal pathway, and deletion of Snail also had similar effects to hamper the development of NSCLC. Next, our rescuing experiments validated that Pokemon ablation-induced suppressing effects on NSCLC cell malignancy were all abrogated by overexpressing Snail. Finally, the in vivo experiments confirmed that silencing of Pokemon downregulated Snail to hamper tumorigenesis of NSCLC cells in xenograft tumor-bearing mice models. Taken together, we firstly uncovered the underlying mechanisms by which the Pokemon/Akt/GSK-3β/Snail signal pathway contributed to the development of NSCLC, and this signal pathway could be potentially used as therapeutic targets for the development of personalized anti-NSCLC drugs.

Comprehensive analysis of FOXM1 immune infiltrates, m6a, glycolysis and ceRNA network in human hepatocellular carcinoma.

Forkhead box M1 (FOXM1) is a member of the Forkhead box (Fox) transcription factor family. It regulates cell mitosis, cell proliferation, and genome stability. However, the relationship between the expression of FOXM1 and the levels of m6a modification, immune infiltration, glycolysis, and ketone body metabolism in HCC has yet to be fully elucidated. Transcriptome and somatic mutation profiles of HCC were downloaded from the TCGA database. Somatic mutations were analyzed by maftools R package and visualized in oncoplots. GO, KEGG and GSEA function enrichment was performed on FOXM1 co-expression using R. We used Cox regression and machine learning algorithms (CIBERSORT, LASSO, random forest, and SVM-RFE) to study the prognostic value of FOXM1 and immune infiltrating characteristic immune cells in HCC. The relationship between FOXM1 and m6A modification, glycolysis, and ketone body metabolism were analyzed by RNA-seq and CHIP-seq. The competing endogenous RNA (ceRNA) network construction relies on the multiMiR R package, ENCORI, and miRNET platforms. FOXM1 is highly expressed in HCC and is associated with a poorer prognosis. At the same time, the expression level of FOXM1 is significantly related to the T, N, and stage. Subsequently, based on the machine learning strategies, we found that the infiltration level of T follicular helper cells (Tfh) was a risk factor affecting the prognosis of HCC patients. The high infiltration of Tfh was significantly related to the poor overall survival rate of HCC. Besides, the CHIP-seq demonstrated that FOXM1 regulates m6a modification by binding to the promoter of IGF2BP3 and affects the glycolytic process by initiating the transcription of HK2 and PKM in HCC. A ceRNA network was successfully obtained, including FOXM1 - has-miR-125-5p - DANCR/MIR4435-2HG ceRNA network related to the prognosis of HCC. Our study implicates that the aberrant infiltration of Tfh associated with FOXM1 is a crucial prognostic factor for HCC patients. FOXM1 regulates genes related to m6a modification and glycolysis at the transcriptional level. Furthermore, the specific ceRNA network can be used as a potential therapeutic target for HCC.

NUF2 is correlated with a poor prognosis and immune infiltration in clear cell renal cell carcinoma

BackgroundClear cell renal cell carcinoma (ccRCC) is one of the most common malignancies. Recently, immunotherapy has been considered a promising treatment for metastatic ccRCC. NUF2 is a crucial component of the Ndc80 complex. NUF2 can stabilize microtubule attachment and is closely related to cell apoptosis and proliferation. This research is dedicated to investigating the role of NUF2 in ccRCC and the possible mechanisms.MethodsFirst, analysis of NUF2 mRNA expression levels in ccRCC and normal tissues by The Cancer Genome Atlas (TCGA) database and further verified by analysis of independent multiple microarray data sets in the Gene Expression Omnibus (GEO) database. Moreover, we evaluated and identified correlations between NUF2 expression, clinicopathologic variable, and overall survival (OS) in ccRCC by various methods. We investigated the relationship between NUF2 and tumor immune infiltration and the expression of corresponding immune cell markers via the Gene Expression Profiling Interactive Analysis (GEPIA) and Tumor Immune Estimation Resource (TIMER) databases. Then, we performed functional enrichment analysis of NUF2 co-expressed genes using R software and protein-protein interactions (PPIs) using the search tool used to retrieve interacting genes/proteins (STRING) databases.ResultsWe discovered that NUF2 mRNA expression was upregulated in ccRCC tissues and was associated with sex, grade, pathological stage, lymph node metastasis, and worse prognosis. In addition, NUF2 was positively linked to tumor immune cells in ccRCC. Moreover, NUF2 was closely related to genetic markers of different immune cells. Finally, functional enrichment and protein–protein interaction (PPI) analysis suggested that NUF2 and its closely related genes may be involved in the regulation of the cell cycle and mitosis. Our results suggested that NUF2 is correlated with a poor prognosis and immune infiltration in ccRCC.

Differential Effects of Overexpression of Wild Type and Kinase-Dead MELK in Fibroblasts and Keratinocytes, Potential Implications for Skin Wound Healing and Cancer.

Maternal embryonic leucine-zipper kinase (MELK) plays a significant role in cell cycle progression, mitosis, cell migration, cell renewal, gene expression, embryogenesis, proliferation, apoptosis, and spliceosome assembly. In addition, MELK is known to be overexpressed in multiple types of cancer and is associated with cancer proliferation. Tumorigenesis shares many similarities with wound healing, in which the rate of cell proliferation is a critical factor. Therefore, this study aimed to determine the involvement of MELK in the regulation of cell division in two cell types involved in this process, namely fibroblasts and keratinocytes. We examined how temporal overexpression of wild-type and kinase-dead MELK kinase variants affect the rate of proliferation, viability, cell cycle, and phosphorylation state of other kinases involved in these processes, such as ERK1/2, AKT1, MAPK9, p38, and p53. We explored if MELK could be used as a therapeutic stimulator of accelerated wound healing via increased proliferation. We observed that aberrant expression of MELK results in abnormal proliferation, altered cell cycle distribution, and decreased viability of the cells, which challenge the utility of MELK in accelerated wound healing. Our results indicate that, at least in healthy cells, any deviation from precisely controlled MELK expression is harmful to fibroblasts and keratinocytes.

Heat shock transcription factors demonstrate a distinct mode of interaction with mitotic chromosomes.

A large number of transcription factors have been shown to bind and interact with mitotic chromosomes, which may promote the efficient reactivation of transcriptional programs following cell division. Although the DNA-binding domain (DBD) contributes strongly to TF behavior, the mitotic behaviors of TFs from the same DBD family may vary. To define the mechanisms governing TF behavior during mitosis in mouse embryonic stem cells, we examined two related TFs: Heat Shock Factor 1 and 2 (HSF1 and HSF2). We found that HSF2 maintains site-specific binding genome-wide during mitosis, whereas HSF1 binding is somewhat decreased. Surprisingly, live-cell imaging shows that both factors appear excluded from mitotic chromosomes to the same degree, and are similarly more dynamic in mitosis than in interphase. Exclusion from mitotic DNA is not due to extrinsic factors like nuclear import and export mechanisms. Rather, we found that the HSF DBDs can coat mitotic chromosomes, and that HSF2 DBD is able to establish site-specific binding. These data further confirm that site-specific binding and chromosome coating are independent properties, and that for some TFs, mitotic behavior is largely determined by the non-DBD regions.

Mitogen-induced defective mitosis transforms neural progenitor cells.

Chromosome instability (CIN) with recurrent copy number alterations is a feature of many solid tumors, including glioblastoma (GBM), yet the genes that regulate cell division are rarely mutated in cancers. Here, we show that the brain-abundant mitogen, platelet-derived growth factor-A (PDGFA) fails to induce the expression of kinetochore and spindle assembly checkpoint genes leading to defective mitosis in neural progenitor cells (NPCs). Using a recently reported in vitro model of the initiation of high-grade gliomas from murine NPCs, we investigated the immediate effects of PDGFA exposure on the nuclear and mitotic phenotypes and patterns of gene and protein expression in NPCs, a putative GBM cell of origin. NPCs divided abnormally in defined media containing PDGFA with P53-dependent effects. In wild-type cells, defective mitosis was associated with P53 activation and cell death, but in some null cells, defective mitosis was tolerated. Surviving cells had unstable genomes and proliferated in the presence of PDGFA accumulating random and clonal chromosomal rearrangements. The outcome of this process was a population of tumorigenic NPCs with recurrent gains and losses of chromosomal regions that were syntenic to those recurrently gained and lost in human GBM. By stimulating proliferation without setting the stage for successful mitosis, PDGFA-transformed NPCs lacking P53 function. Our work describes a mechanism of transformation of NPCs by a brain-associated mitogen, raising the possibility that the unique genomic architecture of GBM is an adaptation to defective mitosis that ensures the survival of affected cells.

Lactate: an intracellular metabolite regulates cell cycle progression

Abstract The Chouchani lab recently reported in Nature that a dynamic intracellular lactate is a physiological regulator for cell cycle progress. They also showed that accumulated lactate in cell mitosis directly binds and inhibits Sentrin/SUMO-specific protease 1 (SENP1) to enrich SUMO2/3-modification of anaphase-promoting complex 4 (APC4), which promotes the degradation of APC/C complexes, leading to mitosis exit.

FTO-stabilized miR-139–5p targets ZNF217 to suppress prostate cancer cell malignancies by inactivating the PI3K/Akt/mTOR signal pathway

As one of the most important demethylases for RNA N6-methyladenosine (m6A) modifications, fat mass and obesity-associated protein (FTO) plays anti-cancer role during prostate cancer (PC), but it is still unclear the detailed molecular mechanisms. Here, this study verified that FTO inactivated the tumor-accelerating PI3K/Akt/mTOR pathway to hamper PC development through regulating the downstream miR-139–5p/zinc finger protein 217 (ZNF217) axis. Through performing clinical analysis, it was revealed that FTO was apparently ablated in the cancerous tissues compared to the normal tissues collected from PC patients, and patients with high-expressed FTO predicted a favorable prognosis. Functional experiments confirmed that overexpression of FTO suppressed cell proliferation, mitosis, epithelial-mesenchymal transition (EMT), tumorigenesis and lung metastasis both in vitro and in vivo. The following mechanical experiments verified that FTO stabilized miR-139–5p to increase its expression levels in a m6A-dependent manner, and elevated miR-139–5p induced degradation of ZNF217 through binding to ZNF217 mRNA, resulting in the inactivation of the PI3K/Akt/mTOR signal pathway. Finally, our rescuing experiments confirmed that overexpressed FTO-induced tumor-suppressing effects on PC cells were abrogated by miR-139–5p ablation and ZNF217 overexpression. Collectively, this study firstly validated that FTO exerted its anti-tumor effects in PC through regulating the miR-139–5p/ZNF217 axis in a m6A-dependent manner, providing novel biomarkers for the advancement of anti-cancer agents for PC treatment.