Oncotarget Zoya N. Demidenko

Knock-down of BCL6 / STAT6 sensitizes primary B cell lymphoma cells for treatment with current therapeutic agents ABSTRACT Primary mediastinal B cell lymphoma (PMBL) is characterized by specific molecular hallmarks including the expression of B Cell Lymphoma factor 6 (BCL6) and the presence of the activated Signal Transducers and Activators of Transcription factor 6 (STAT6). Recently we have shown that combined targeting of BCL6 and activated STAT6 by specific chemical inhibitors in PMBL resulted in additive efficacy regarding their negative effects on cell viability. Given that despite general efficient immuno-chemotherapy in PMBL the  delayed  treatment-related sequelae  remains still a main challenge, we analyzed the role of BCL6 and activated STAT6 in the sensitivity of PMBL cells to the current treatment components. We found that the knock-down of BCL6 / STAT6 by siRNA sensitized the PMBL cells to the effects of R-CHOP components in two of three PMBL cell lines. In one cell line,

Whole-exome sequencing identifies ATRX mutation as a key molecular determinant in lower-grade glioma ABSTRACT The molecular foundations of lower-grade gliomas (LGGs)—astrocytoma, oligodendroglioma, and oligoastrocytoma—remain less well characterized than those of their fully malignant counterpart, glioblastoma. Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) likely represent initiating pathogenic events. However, while IDH mutations appear to dramatically alter cellular epigenomic landscapes, definitive downstream transformative mechanisms have not been characterized. It remains likely, therefore, that additional genomic abnormalities collaborate with IDH mutation to drive oncogenesis in LGG. We performed whole exome sequencing in 4 LGGs, followed by focused resequencing in an additional 28, and found a high incidence of mutations in the ATRX gene (α thalassemia/mental retardation syndrome X-linked). ATRX forms a core component of a chromatin remodeling complex active in telomer

Reactivation of codogenic endogenous retroviral (ERV) envelope genes in human endometrial carcinoma and prestages: Emergence of new molecular targets. ABSTRACT Endometrial carcinoma (EnCa) is the most common invasive gynaecologic carcinoma. Over 85% of EnCa are classified as endometrioid, expressing steroid hormone receptors and mostly involving pathological prestages. Human endogenous retroviruses (ERV) are chromosomally integrated genes, account for about 8% of the human genome and are implicated in the etiology of carcinomas. The majority of ERV envelope (env) coding genes are either not present or not consistently represented between common gene expression microarrays. The aim of this study was to analyse the absolute gene expression of all known 21 ERV env genes including 19 codogenic and two env genes with premature stop codons in EnCa, endometrium as well as in hyperplasia and polyps. For EnCa seven env genes had high expression with >200 mol/ng cDNA (e.g. envH1-3, Syncytin-1

Chronological lifespan in stationary culture: From yeast to human cells Abstract This first paper defines the field, providing description of the phenomenon, its mechanism and the ways of pharmacological manipulation. It illuminates the place of yeast CS in aging research and its indirect (via common signaling pathways) relevance to cancer and organismal aging. It also rules out altruistic (programmed) aging of yeast because no one would suspect altruistic nature of cancer cells.  https://www.researchgate.net/scientific-contributions/39445053_Zoya_N_Demidenko oncotarget removed from pubmed Zoya Demidenko Dr. Zoya N. Demidenko Zoya N. Demidenko , Ph.D. is Executive Manager of the Oncotarget journal . Oncotarget publishes high-impact research papers of general interest and outstanding significance and novelty in all areas of biology and medicine: in translational, basic and clinical research including but not limited to cancer research, oncogenes, oncoproteins and tumor suppressors, si

Hypoxia suppresses conversion from proliferative arrest to cellular senescence Abstract Unlike reversible quiescence, cellular senescence is characterized by a large flat cell morphology, β-gal staining and irreversible loss of regenerative (i.e., replicative) potential. Conversion from proliferative arrest to irreversible senescence, a process named geroconversion, is driven in part by growth-promoting pathways such as mammalian target of rapamycin (mTOR). During cell cycle arrest, mTOR converts reversible arrest into senescence. Inhibitors of mTOR can suppress geroconversion, maintaining quiescence instead. It was shown that hypoxia inhibits mTOR. Therefore, we suggest that hypoxia may suppress geroconversion. Here we tested this hypothesis. In HT-p21-9 cells, expression of inducible p21 caused cell cycle arrest without inhibiting mTOR, leading to senescence. Hypoxia did not prevent p21 induction and proliferative arrest, but instead inhibited the mTOR pathway and geroconversion. Exp

Hyper-mitogenic drive coexists with mitotic incompetence in senescent cells Abstract When the cell cycle is arrested, even though growth-promoting pathways such as mTOR are still active, then cells senesce. For example, induction of either p21 or p16 arrests the cell cycle without inhibiting mTOR, which, in turn, converts p21/p16-induced arrest into senescence (geroconversion). Here we show that geroconversion is accompanied by dramatic accumulation of cyclin D1 followed by cyclin E and replicative stress. When p21 was switched off, senescent cells (despite their loss of proliferative potential) progressed through S phase, and levels of cyclins D1 and E dropped. Most cells entered mitosis and then died, either during mitotic arrest or after mitotic slippage, or underwent endoreduplication. Next, we investigated whether inhibition of mTOR would prevent accumulation of cyclins and loss of mitotic competence in p21-arrested cells. Both nutlin-3, which inhibits mTOR in these cells, and rap

Recent discoveries in the cycling, growing and aging of the p53 field Abstract The P53 gene and it product p53 protein is the most studied tumor suppressor, which was considered as oncogene for two decades until 1990. More than 60 thousand papers on the topic of p53 has been abstracted in Pubmed. What yet could be discovered about its role in cell death, growth arrest and apoptosis, as well as a mediator of the therapeutic effect of anticancer drugs. Still during recent few years even more amazing discoveries have been done. Here we review such topics as suppression of epigenetic silencing of a large number of non-coding RNAs, role of p53 in suppression of the senescence phenotype, inhibition of oncogenic metabolism, protection of normal cells from chemotherapy and even tumor suppression without apoptosis and cell cycle arrest. https://www.researchgate.net/scientific-contributions/39445053_Zoya_N_Demidenko oncotarget submission Zoya Demidenko Dr. Zoya N. Demidenko Zoya N. Demidenko ,

MEK drives cyclin D1 hyperelevation during geroconversion Abstract When the cell cycle becomes arrested, MTOR (mechanistic Target of Rapamycin) converts reversible arrest into senescence (geroconversion). Hyperexpression of cyclin D1 is a universal marker of senescence along with hypertrophy, beta-Gal staining and loss of replicative/regenerative potential (RP), namely, the ability to restart proliferation when the cell cycle is released. Inhibition of MTOR decelerates geroconversion, although only partially decreases cyclin D1. Here we show that in p21- and p16-induced senescence, inhibitors of mitogen-activated/extracellular signal-regulated kinase (MEK) (U0126, PD184352 and siRNA) completely prevented cyclin D1 accumulation, making it undetectable. We also used MEL10 cells in which MEK inhibitors do not inhibit MTOR. In such cells, U0126 by itself induced senescence that was remarkably cyclin D1 negative. In contrast, inhibition of cyclin-dependent kinase (CDK) 4/6 by PD0332991 caus

S6K in geroconversion Abstract Markers of cellular senescence depend in part on the MTOR (mechanistic target of rapamycin) pathway. MTOR participates in geroconversion, a conversion from reversible cell cycle arrest to irreversible senescence. Recently we demonstrated that hyper-induction of cyclin D1 during geroconversion was mostly dependent on MEK, whereas rapamycin only partially inhibited cyclin D1 accumulation. Here we show that, while not affecting cyclin D1, siRNA for p70S6K partially prevented loss of RP (replicative/regenerative potential) during p21-induced cell cycle arrest. Similarly, an inhibitor of p70 S6 kinase (PF-4708671) partially inhibited phosphorylation of S6 and preserved RP, while only marginally prevented cyclin D1 induction. Thus S6K and MEK play different roles in geroconversion.  https://www.researchgate.net/scientific-contributions/39445053_Zoya_N_Demidenko oncotarget. impact factor Zoya Demidenko Dr. Zoya N. Demidenko Zoya N. Demidenko , Ph.D. is Executi

Elimination of Proliferating Cells Unmasks the Shift from Senescence to Quiescence Caused by Rapamycin Abstract Background Depending on cellular context, p53-inducing agents (such as nutlin-3a) cause different outcomes including reversible quiescence and irreversible senescence. Inhibition of mTOR shifts the balance from senescence to quiescence. In cell lines with incomplete responses to p53, this shift may be difficult to document because of a high proportion of proliferating cells contaminating arrested (quiescent and senescent) cells. This problem also complicates the study of senescence caused by minimal levels of p21 that are capable to arrest a few cells. Methodology During induction of senescence by low levels of endogenous p53 and ectopic p21, cells were co-treated with nocodazole, which eliminated proliferating cells. As a result, only senescent and quiescent cells remained. Results and Discussion This approach revealed that rapamycin efficiently converted nutlin-induced-sene

Oncotarget .  Zoya N. Demidenko  Welcome to oncotarget.net, a website about  Oncotarget , a peer-reviewed open access research journal focusing on all topics surrounding cancer research. Oncotarget is published by Impact Journals of Orchard Park, New York. Impact Journals meets the standards established Wellcome Trust Publisher Requirements and is included on the Wellcome Trust List of Compliant Publishers.  Oncotarget is proud to have multiple Nobel Prize winning members on its editorial board, in addition to editors who have won the Lasker Prize and other prestigious recognitions. The open-access model employed by Oncotarget allows for free dissemination of thoroughly vetted peer-reviewed research material to the general public, leading to bigger and more frequent scientific breakthroughs. Because of Oncotarget’s uniquely varied scope, the journal has consistently published research on a wide range of subject areas, allowing readers to access an unparalleled diversity of knowledge in