Cycle Progression
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2021 ◽  
Viola Introini ◽  
Gururaj Rao Kidiyoor ◽  
Giancarlo Porcella ◽  
Marco Foiani ◽  
Pietro Cicuta ◽  

The cell nucleus plays a central role in several key cellular processes, including chromosome organisation, replication and transcription. Recent work intriguingly suggests an association between nuclear mechanics and cell-cycle progression, but many aspects of this connection remain unexplored. Here, by monitoring nuclear shape fluctuations at different cell cycle stages, we uncover increasing inward fluctuations in late G2 and early mitosis, which are initially transient, but develop into instabilities that culminate into nuclear-envelope breakdown in mitosis. Perturbation experiments and correlation analysis reveal an association of these processes with chromatin condensation. We propose that the contrasting forces between an extensile stress and centripetal pulling from chromatin condensation could link mechanically chromosome condensation and nuclear-envelope breakdown, the two main nuclear processes during mitosis.

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5900
Antonin Bouroumeau ◽  
Lucile Bussot ◽  
Sieme Hamaidia ◽  
Andrea Garcìa-Sandoval ◽  
Anna Bergan-Dahl ◽  

R-CHOP immuno-chemotherapy significantly improved clinical management of diffuse large B-cell lymphoma (DLBCL). However, 30–40% of DLBCL patients still present a refractory disease or relapse. Most of the prognostic markers identified to date fail to accurately stratify high-risk DLBCL patients. We have previously shown that the nuclear protein CYCLON is associated with DLBCL disease progression and resistance to anti-CD20 immunotherapy in preclinical models. We also recently reported that it also represents a potent predictor of refractory disease and relapse in a retrospective DLBCL cohort. However, only sparse data are available to predict the potential biological role of CYCLON and how it might exert its adverse effects on lymphoma cells. Here, we characterized the protein interaction network of CYCLON, connecting this protein to the nucleolus, RNA processing, MYC signaling and cell cycle progression. Among this network, NPM1, a nucleolar multi-functional protein frequently deregulated in cancer, emerged as another potential target related to treatment resistance in DLBCL. Immunohistochemistry evaluation of CYCLON and NPM1 revealed that their co-expression is strongly related to inferior prognosis in DLBCL. More specifically, alternative sub-cellular localizations of the proteins (extra-nucleolar CYCLON and pan-cellular NPM1) represent independent predictive factors specifically associated to R-CHOP refractory DLBCL patients, which could allow them to be orientated towards risk-adapted or novel targeted therapies.

Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1751
Elizabeth Mazzio ◽  
Nzinga Mack ◽  
Ramesh B. Badisa ◽  
Karam F. A. Soliman

A number of aggressive human malignant tumors are characterized by an intensified glycolytic rate, over-expression of lactic acid dehydrogenase A (LDHA), and subsequent lactate accumulation, all of which contribute toward an acidic peri-cellular immunosuppressive tumor microenvironment (TME). While recent focus has been directed at how to inhibit LDHA, it is now becoming clear that multiple isozymes of LDH must be simultaneously inhibited in order to fully suppress lactic acid and halt glycolysis. In this work we explore the biochemical and genomic consequences of an applied triple LDH isozyme inhibitor (A, B, and C) (GNE-140) in MDA-MB-231 triple-negative breast cancer cells (TNBC) cells. The findings confirm that GNE-140 does in fact, fully block the production of lactic acid, which also results in a block of glucose utilization and severe impedance of the glycolytic pathway. Without a fully functional glycolytic pathway, breast cancer cells continue to thrive, sustain viability, produce ample energy, and maintain mitochondrial potential (ΔΨM). The only observable negative consequence of GNE-140 in this work, was the attenuation of cell division, evident in both 2D and 3D cultures and occurring in fully viable cells. Of important note, the cytostatic effects were not reversed by the addition of exogenous (+) lactic acid. While the effects of GNE-140 on the whole transcriptome were mild (12 up-regulated differential expressed genes (DEGs); 77 down-regulated DEGs) out of the 48,226 evaluated, the down-regulated DEGS collectively centered around a loss of genes related to mitosis, cell cycle, GO/G1–G1/S transition, and DNA replication. These data were also observed with digital florescence cytometry and flow cytometry, both corroborating a G0/G1 phase blockage. In conclusion, the findings in this work suggest there is an unknown element linking LDH enzyme activity to cell cycle progression, and this factor is completely independent of lactic acid. The data also establish that complete inhibition of LDH in cancer cells is not a detriment to cell viability or basic production of energy.

2021 ◽  
Vol 39 (1) ◽  
SuXia Wang ◽  
Hui Zhang ◽  
HaiTing Liu ◽  
XiangYu Guo ◽  
RanRan Ma ◽  

2021 ◽  
Vol 219 (1) ◽  
Bassem D. Khalil ◽  
Roberto Sanchez ◽  
Tasrina Rahman ◽  
Carolina Rodriguez-Tirado ◽  
Stefan Moritsch ◽  

We describe the discovery of an agonist of the nuclear receptor NR2F1 that specifically activates dormancy programs in malignant cells. The agonist led to a self-regulated increase in NR2F1 mRNA and protein and downstream transcription of a novel dormancy program. This program led to growth arrest of an HNSCC PDX line, human cell lines, and patient-derived organoids in 3D cultures and in vivo. This effect was lost when NR2F1 was knocked out by CRISPR-Cas9. RNA sequencing revealed that agonist treatment induces transcriptional changes associated with inhibition of cell cycle progression and mTOR signaling, metastasis suppression, and induction of a neural crest lineage program. In mice, agonist treatment resulted in inhibition of lung HNSCC metastasis, even after cessation of the treatment, where disseminated tumor cells displayed an NR2F1hi/p27hi/Ki-67lo/p-S6lo phenotype and remained in a dormant single-cell state. Our work provides proof of principle supporting the use of NR2F1 agonists to induce dormancy as a therapeutic strategy to prevent metastasis.

2021 ◽  
Ao Qian ◽  
Gang Huo ◽  
Xiaoshu Wang ◽  
Jiamin Mou ◽  
Dong Gao ◽  

Abstract Background PLK3, a gene played an important role in cell cycle progression and stress response, was identified in different carcinomas. However, the PLK3 expression, molecular characteristics, and prognostic value in glioma still remained unknown. Methods Total 2265 glioma samples from the CGGA RNA-seq, TCGA RNA-seq, CGGA microarray, GSE16011, as well as their clinical information and genomic profiles were selected in our research. Survival analysis based on Kaplan–Meier and Cox proportional hazard model methods was performed to evaluate the prognostic value. Results Expression of PLK3 was compared in different WHO grade, isocitrate dehydrogenase (IDH) status, and molecular subtype of gliomas. We found that increased level of PLK3 was associated with malignancy and invasiveness of glioma, and high expression of PLK3 may represent malignant entities with amplification of driver oncogenes and deletion of suppressor genes. Moreover, PLK3 played a crucial role in inflammatory and immune response, and was involved in suppressive T cell anti-tumor functions. Furthermore, PLK3 was synergistic with other checkpoint members in glioma. Finally, high expression of PLK3 was associated with malignant process and reduced survival in patients with glioma. Conclusion PLK3 may serve as an indicator of poor prognosis in glioma and a potential target for immunotherapy of glioma. These results demonstrated that PLK3 may serve as a biomarker and a potential target of glioma.

2021 ◽  
Piwei Huang ◽  
Minghui Wei ◽  
Shufan Ji ◽  
Mitra Fowdur ◽  
maolin he

Abstract BackgroundRibosomal protein L34 (RPL34) is a member of the L34E ribosomal protein family containing zinc finger domains. This protein plays a key role in regulating the apoptosis, cell cycle progression and proliferation of various cancer including osteosarcoma (OS). The purpose of this study is to clarify the expression of RPL34 in osteosarcoma cells and its molecular mechanism of regulating osteosarcoma cells. MethodsThe expression levels of c-Myc and RPL34 were detected by qRT-PCR and Western blot. Luciferase reporter assays and chromatin immunoprecipitation (ChIP) were used to analyse the binding site of c-Myc and RPL34. ResultsThe results showed that c-Myc binds to the E-box region in the RPL34 promoter to regulate RPL34 expression. The results indicated that RPL34 regulates osteosarcoma cells proliferation through c-Myc/RPL34 signaling axis. This research may provide new ideas for targeted therapy of OS. Conclusion RPL34 regulates osteosarcoma cells proliferation through c-Myc/RPL34 signaling axis.

2021 ◽  
Nadine Pollak ◽  
Aline Lindner ◽  
Dirke Imig ◽  
Karsten Kuritz ◽  
Jacques S. Fritze ◽  

Extrinsic apoptosis relies on TNF-family receptor activation by immune cells or receptor-activating biologics. Here, we monitored cell cycle progression at minutes resolution to relate apoptosis kinetics and cell-to-cell heterogeneities in death decisions to cell cycle phases. Interestingly, we found that cells in S phase delay TRAIL receptor-induced death in favour for mitosis, thereby passing on an apoptosis-primed state to their offspring. This translates into two distinct fates, apoptosis execution post mitosis or cell survival from inefficient apoptosis. Transmitotic resistance is linked to Mcl-1 upregulation and increased accumulation at mitochondria from mid S phase onwards, which allows cells to pass through mitosis with activated caspase-8, and with cells escaping apoptosis after mitosis sustaining sublethal DNA damage. Antagonizing Mcl-1 suppresses cell cycle-dependent delays in apoptosis, prevents apoptosis-resistant progression through mitosis and averts unwanted survival from apoptosis induction. Cell cycle progression therefore modulates signal transduction during extrinsic apoptosis, with Mcl-1 governing decision making between death, proliferation and survival. Cell cycle progression thus is a crucial process from which cell-to-cell heterogeneities in fates and treatment outcomes emerge in isogenic cell populations during extrinsic apoptosis.

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0258996
Wandayi Emmanuel Amlabu ◽  
Cynthia Mmalebna Amisigo ◽  
Christine Achiaa Antwi ◽  
Gordon Akanzuwine Awandare ◽  
Theresa Manful Gwira

In the midst of numerous setbacks that beclouds the fight against leishmaniasis; a neglected tropical disease, the search for new chemotherapeutics against this disease is of utmost importance. Leishmaniasis is a disease closely associated with poverty and endemic in Africa, Asia, southern Europe and the Americas. It is caused by parasites of the genus Leishmania and transmitted by a sandfly vector. In this study, we evaluated the antileishmanial potency of eighteen pathogen box compounds and elucidated their biosafety and possible mechanisms of action against Leishmania donovani promastigotes and amastigotes in vitro. IC50s range of 0.12±0.15 to >6.25 μg/ml and 0.13±0.004 to >6.25μg/ml were observed for the promastigotes and amastigotes, respectively. We demonstrated the ability of some of the compounds to cause cytocidal effect on the parasites, induce increased production of reactive oxygen species (ROS), disrupt the normal parasite morphology and cause the accumulation of parasites at the DNA synthesis phase of the cell cycle. We recommend a further in vivo study on these compounds to validate the findings.

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0260204
Murshed H. Sarkar ◽  
Ryoji Yagi ◽  
Yukihiro Endo ◽  
Ryo Koyama-Nasu ◽  
Yangsong Wang ◽  

While IFNγ is a well-known cytokine that actively promotes the type I immune response, it is also known to suppress the type II response by inhibiting the differentiation and proliferation of Th2 cells. However, the mechanism by which IFNγ suppresses Th2 cell proliferation is still not fully understood. We found that IFNγ decreases the expression of growth factor independent-1 transcriptional repressor (GFI1) in Th2 cells, resulting in the inhibition of Th2 cell proliferation. The deletion of the Gfi1 gene in Th2 cells results in the failure of their proliferation, accompanied by an impaired cell cycle progression. In contrast, the enforced expression of GFI1 restores the defective Th2 cell proliferation, even in the presence of IFNγ. These results demonstrate that GFI1 is a key molecule in the IFNγ-mediated inhibition of Th2 cell proliferation.

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