Publications by authors named "Francois M Vallette"

89 Publications

TOM20-mediated transfer of Bcl2 from ER to MAM and mitochondria upon induction of apoptosis.

Cell Death Dis 2021 Feb 15;12(2):182. Epub 2021 Feb 15.

CRCINA, INSERM, Université d'Angers, Université de Nantes, Nantes, France.

In this work, we have explored the subcellular localization of Bcl2, a major antiapoptotic protein. In U251 glioma cells, we found that Bcl2 is localized mainly in the ER and is translocated to MAM and mitochondria upon induction of apoptosis; this mitochondrial transfer was not restricted to the demonstrator cell line, even if cell-specific modulations exist. We found that the Bcl2/mitochondria interaction is controlled by TOM20, a protein that belongs to the protein import machinery of the mitochondrial outer membrane. The expression of a small domain of interaction of TOM20 with Bcl2 potentiates its anti-apoptotic properties, which suggests that the Bcl2-TOM20 interaction is proapoptotic. The role of MAM and TOM20 in Bcl2 apoptotic mitochondrial localization and function has been confirmed in a yeast model in which the ER-mitochondria encounter structure (ERMES) complex (required for MAM stability in yeast) has been disrupted. Bcl2-TOM20 interaction is thus an additional player in the control of apoptosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41419-021-03471-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884705PMC
February 2021

Drug Resistance in Glioblastoma: The Two Faces of Oxidative Stress.

Front Mol Biosci 2020 27;7:620677. Epub 2021 Jan 27.

Université de Nantes, INSERM, CRCINA, Nantes, France.

Glioblastomas (GBM) are the most common primary brain tumor with a median survival of 15 months. A population of cells with stem cell properties (glioblastoma stem cells, GSCs) drives the initiation and progression of GBM and is localized in specialized microenvironments which support their behavior. GBM are characterized as extremely resistant to therapy, resulting in tumor recurrence. Reactive oxygen species (ROS) control the cellular stability by influencing different signaling pathways. Normally, redox systems prevent cell oxidative damage; however, in gliomagenesis, the cellular redox mechanisms are highly impaired. Herein we review the dual nature of the redox status in drug resistance. ROS generation in tumor cells affects the cell cycle and is involved in tumor progression and drug resistance in GBM. However, excess ROS production has been found to induce cell death programs such as apoptosis and autophagy. Since GBM cells have a high metabolic rate and produce high levels of ROS, metabolic adaptation in these cells plays an essential role in resistance to oxidative stress-induced cell death. Finally, the microenvironment with the stromal components participates in the enhancement of the oxidative stress to promote tumor progression and drug resistance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmolb.2020.620677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873048PMC
January 2021

Anti-PD1 therapy induces lymphocyte-derived exosomal miRNA-4315 release inhibiting Bim-mediated apoptosis of tumor cells.

Cell Death Dis 2020 12 11;11(12):1048. Epub 2020 Dec 11.

CRCINA, INSERM, Université de Nantes, Nantes, France.

Anti-PD1 immunotherapy, as a single agent or in combination with standard chemotherapies, has significantly improved the outcome of many patients with cancers. However, resistance to anti-PD1 antibodies often decreases the long-term therapeutic benefits. Despite this observation in clinical practice, the molecular mechanisms associated with resistance to anti-PD1 antibody therapy have not yet been elucidated. To identify the mechanisms of resistance associated with anti-PD1 antibody therapy, we developed cellular models including purified T cells and different cancer cell lines from glioblastoma, lung adenocarcinoma, breast cancer and ovarian carcinoma. A murine model of lung cancer was also used. Longitudinal blood samples of patients treated with anti-PD1 therapy were also used to perform a proof-of-concept study of our findings. We found that anti-PD1 exposure of T-cell promotes an enrichment of exosomal miRNA-4315. We also noted that exosomal miRNA-4315 induced a phenomenon of apopto-resistance to conventional chemotherapies in cancer cells receiving exosomal miRNA-4315. At molecular level, we discern that the apopto-resistance phenomenon was associated with the miRNA-4315-mediated downregulation of Bim, a proapoptotic protein. In cellular and mice models, we observed that the BH3 mimetic agent ABT263 circumvented this resistance. A longitudinal study using patient blood showed that miRNA-4315 and cytochrome c can be used to define the time period during which the addition of ABT263 therapy may effectively increase cancer cell death and bypass anti-PD1 resistance.This work provides a blood biomarker (exosomal miRNA-4315) for patient stratification developing a phenomenon of resistance to anti-PD1 antibody therapy and also identifies a therapeutic alternative (the use of a BH3 mimetic drug) to limit this resistance phenomenon.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41419-020-03224-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733505PMC
December 2020

Mitochondria transfer from tumor-activated stromal cells (TASC) to primary Glioblastoma cells.

Biochem Biophys Res Commun 2020 Nov 15;533(1):139-147. Epub 2020 Sep 15.

Université de Nantes, INSERM, CRCINA, Nantes, 44007, France; CHU de Nantes, Department of Neurosurgery, Nantes, 44007, France. Electronic address:

The tumor microenvironment (TME) controls many aspects of cancer development but little is known about its effect in Glioblastoma (GBM), the main brain tumor in adults. Tumor-activated stromal cell (TASC) population, a component of TME in GBM, was induced in vitro by incubation of MSCs with culture media conditioned by primary cultures of GBM under 3D/organoid conditions. We observed mitochondrial transfer by Tunneling Nanotubes (TNT), extracellular vesicles (EV) and cannibalism from the TASC to GBM and analyzed its effect on both proliferation and survival. We created primary cultures of GBM or TASC in which we have eliminated mitochondrial DNA [Rho 0 (ρ) cells]. We found that TASC, as described in other cancers, increased GBM proliferation and resistance to standard treatments (radiotherapy and chemotherapy). We analyzed the incorporation of purified mitochondria by ρ and ρ cells and a derived mathematical model taught us that ρ cells incorporate more rapidly pure mitochondria than ρ cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2020.08.101DOI Listing
November 2020

N6-Adenosine Methylation of miRNA-200b-3p Influences Its Functionality and Is a Theranostic Tool.

Mol Ther Nucleic Acids 2020 Aug 14;22:72-83. Epub 2020 Aug 14.

CRCINA, INSERM, Université de Nantes, Nantes, France; Equipe Apoptose et Progression Tumorale, LaBCT, Institut de Cancérologie de l'Ouest, Saint Herblain, France; Cancéropole Grand-Ouest, Réseau Niches et Epigénétique des Tumeurs (NET), Nantes, France; EpiSAVMEN Network (Région Pays de la Loire), Nantes, France; LabEX IGO, Université de Nantes, Nantes, France. Electronic address:

MicroRNAs (miRNAs or miRs) play crucial roles in biological and pathological processes. Some miRNAs also appear as promising biomarkers and therapeutic tools. However, the epitranscriptomic regulation of miRNAs is not yet fully elucidated in all of their fields of application. We report that adenosine methylation of miR-200b-3p inhibits its repressive function toward its mRNA targets such as XIAP by blocking the formation of the miRNA/3' UTR duplex. Our data indicate that the adenosine methylation of miR-200b-3p is associated with the survival of glioblastoma patients. Collectively, our data support the idea that the adenosine methylation of miR-200b-3p can be used as a prodrug having a selective cytotoxicity against cancer cells (while being harmless to peripheral blood mononuclear cells [PBMCs], astrocytes, neurons, and hepatocytes).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.omtn.2020.08.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490450PMC
August 2020

Sphingolipid distribution at mitochondria-associated membranes (MAMs) upon induction of apoptosis.

J Lipid Res 2020 07 29;61(7):1025-1037. Epub 2020 Apr 29.

CRCINA, INSERM, Université d'Angers, Université de Nantes, Nantes, France

The levels and composition of sphingolipids and related metabolites are altered in aging and in common disorders such as diabetes and cancers, as well as in neurodegenerative, cardiovascular, and respiratory diseases. Changes in sphingolipids have been implicated as being an essential step in mitochondria-driven cell death. However, little is known about the precise sphingolipid composition and modulation in mitochondria or related organelles. Here, we used LC-MS/MS to analyze the presence of key components of the ceramide metabolic pathway in vivo and in vitro in purified ER, mitochondria-associated membranes (MAMs), and mitochondria. Specifically, we analyzed the sphingolipids in the three pathways that generate ceramide: sphinganine in the de novo ceramide pathway, SM in the breakdown pathway, and sphingosine in the salvage pathway. We observed sphingolipid profiles in mouse liver, mouse brain, and a human glioma cell line (U251). We analyzed the quantitative and qualitative changes of these sphingolipids during staurosporine-induced apoptosis in U251 cells. Ceramide (especially C16-ceramide) levels increased during early apoptosis possibly through a conversion from mitochondrial sphinganine and SM, but sphingosine and lactosyl- and glycosyl-ceramide levels were unaffected. We also found that ceramide generation is enhanced in mitochondria when SM levels are decreased in the MAM. This decrease was associated with an increase in acid sphingomyelinase activity in MAM. We conclude that meaningful sphingolipid modifications occur in MAM, the mitochondria, and the ER during the early steps of apoptosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1194/jlr.RA120000628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328052PMC
July 2020

Radiotherapy-induced overexpression of exosomal miRNA-378a-3p in cancer cells limits natural killer cells cytotoxicity.

Epigenomics 2020 03 8;12(5):397-408. Epub 2020 Apr 8.

CRCINA, INSERM, Université de Nantes, Nantes 44000, France.

We here hypothesized that tumor-derived exosomal miRNA (TexomiR) released from irradiated tumors may play a role in the tumor cells escape to natural killer (NK) cells. Our study included the use of different cancer cell lines, blood biopsies of xenograph mice model and patients treated with radiotherapy. The irradiation of cancer cells promotes the TET2-mediated demethylation of miR-378 promoter, miR-378a-3p overexpression and its loading in exosomes, inducing the decrease of granzyme-B (GZMB) secretion by NK cells. An inverse correlation between TexomiR-378a-3p and GZMB was observed in murine and human blood samples. Our work identifies TexomiR-378a-3p as a molecular signature associated with the loss of NK cells cytotoxicity via the decrease of GZMB expression upon radiotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/epi-2019-0193DOI Listing
March 2020

Cytosine methylation of mature microRNAs inhibits their functions and is associated with poor prognosis in glioblastoma multiforme.

Mol Cancer 2020 02 25;19(1):36. Epub 2020 Feb 25.

CRCINA, INSERM, Université de Nantes, Nantes, France.

Background: Literature reports that mature microRNA (miRNA) can be methylated at adenosine, guanosine and cytosine. However, the molecular mechanisms involved in cytosine methylation of miRNAs have not yet been fully elucidated. Here we investigated the biological role and underlying mechanism of cytosine methylation in miRNAs in glioblastoma multiforme (GBM).

Methods: RNA immunoprecipitation with the anti-5methylcytosine (5mC) antibody followed by Array, ELISA, dot blot, incorporation of a radio-labelled methyl group in miRNA, and miRNA bisulfite sequencing were perfomred to detect the cytosine methylation in mature miRNA. Cross-Linking immunoprecipiation qPCR, transfection with methylation/unmethylated mimic miRNA, luciferase promoter reporter plasmid, Biotin-tagged 3'UTR/mRNA or miRNA experiments and in vivo assays were used to investigate the role of methylated miRNAs. Finally, the prognostic value of methylated miRNAs was analyzed in a cohorte of GBM pateints.

Results: Our study reveals that a significant fraction of miRNAs contains 5mC. Cellular experiments show that DNMT3A/AGO4 methylated miRNAs at cytosine residues inhibit the formation of miRNA/mRNA duplex and leading to the loss of their repressive function towards gene expression. In vivo experiments show that cytosine-methylation of miRNA abolishes the tumor suppressor function of miRNA-181a-5p miRNA for example. Our study also reveals that cytosine-methylation of miRNA-181a-5p results is associated a poor prognosis in GBM patients.

Conclusion: Together, our results indicate that the DNMT3A/AGO4-mediated cytosine methylation of miRNA negatively.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12943-020-01155-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041276PMC
February 2020

Cell-free circulating epimarks in cancer monitoring.

Epigenomics 2020 01 9;12(2):145-155. Epub 2020 Jan 9.

CRCINA, INSERM, Université de Nantes, Nantes, France.

Cancer numbers increasing, cases heterogeneity and the drug resistance emergence have pushed scientists to search for innovative solutions for patients and epimutations can be one. Methylated DNA, modified nucleosomes and noncoding RNAs are found in all cells, including tumor cells. They are intracellular actors but also have intercellular communication roles, being released in extracellular environment and in different body fluids. Here, we reviewed current literature on the use of these blood circulating epimarks in cancer monitoring. What stands out is that epimarkers must be considered as 'real time' images of the tumor, and can be isolated without invasive methods. In the future, the real challenge lies in the development of specific, sensitive, fast and clinically applicable detection and analysis methods of epimarkers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/epi-2019-0170DOI Listing
January 2020

Identification of a transient state during the acquisition of temozolomide resistance in glioblastoma.

Cell Death Dis 2020 01 6;11(1):19. Epub 2020 Jan 6.

CRCINA, INSERM, Université d'Angers, Université de Nantes, Nantes, France.

Drug resistance limits the therapeutic efficacy in cancers and leads to tumor recurrence through ill-defined mechanisms. Glioblastoma (GBM) are the deadliest brain tumors in adults. GBM, at diagnosis or after treatment, are resistant to temozolomide (TMZ), the standard chemotherapy. To better understand the acquisition of this resistance, we performed a longitudinal study, using a combination of mathematical models, RNA sequencing, single cell analyses, functional and drug assays in a human glioma cell line (U251). After an initial response characterized by cell death induction, cells entered a transient state defined by slow growth, a distinct morphology and a shift of metabolism. Specific genes expression associated to this population revealed chromatin remodeling. Indeed, the histone deacetylase inhibitor trichostatin (TSA), specifically eliminated this population and thus prevented the appearance of fast growing TMZ-resistant cells. In conclusion, we have identified in glioblastoma a population with tolerant-like features, which could constitute a therapeutic target.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41419-019-2200-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944699PMC
January 2020

Diuron exposure and Akt overexpression promote glioma formation through DNA hypomethylation.

Clin Epigenetics 2019 11 14;11(1):159. Epub 2019 Nov 14.

CRCINA, INSERM, Université de Nantes, Nantes, France.

Background: Diuron is an environmental component listed as a likely human carcinogen. Several other studies report that diuron can be oncogenic for bladder, urothelial, skin, and mammary cells. No study mentions the putative effect of diuron on the glioma occurrence.

Objectives: We here wanted to investigate the effects of diuron exposure on the glioma occurrence while wishing to incriminate a putative implication of DNA methylation modulation in this process.

Methods: In in vivo model of glioma, diuron exposure was firstly compared or combined with oncogenic overexpressions already known to promote gliomagenesis. ELISA quantifying the 5-methylcytosine level on DNA was performed to examine the global DNA methylation level. Quantitative real-time polymerase chain reaction and proximity ligation in situ assay were performed to identify the molecular causes of the diuron-induced changes of DNA methylation. The signatures diuron-induced changes of DNA methylation were analyzed in a cohort of 23 GBM patients.

Results: Diuron exposure is not sufficient to promote glioma, such as the oncogenic overexpression of Akt or Ras. However, the combination of diuron exposure and Akt overexpression promotes glioma. We observed that the diuron/Akt-induced glioma is characterized by three phenotypic signatures characterizing cancer cells: a global DNA hypomethylation, a loss of sensitivity to cell death induction, and a gain of signals of immune escape. Our data associated these phenotypes with three aberrant DNA methylation signatures: the LLT1, PD-L1, and Bcl-w hypomethylations. Strikingly, we observed that these three concomitant hypomethylations were only observed in GBM patients having a potential exposure to diuron via their professional activity.

Conclusions: As single player, diuron is not an oncogenic of glioma, but it can participate to the glioma formation in association with other events (also devoid of oncogenic property as single player) such as Akt overexpression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13148-019-0759-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854743PMC
November 2019

Tumor cells hijack enteric glia to activate colon cancer stem cells and stimulate tumorigenesis.

EBioMedicine 2019 Nov 26;49:172-188. Epub 2019 Oct 26.

Bretagne Loire University, Nantes University, INSERM 1235, IMAD, The Enteric Nervous System in Gut and Brain Disorders, Nantes, France; Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA. Electronic address:

Background: Colon cancer stem cells (CSCs), considered responsible for tumor initiation and cancer relapse, are constantly exposed to regulatory cues emanating from neighboring cells present in the tumor microenvironment. Among these cells are enteric glial cells (EGCs) that are potent regulators of the epithelium functions in a healthy intestine. However, whether EGCs impact CSC-driven tumorigenesis remains unknown.

Methods: Impact of human EGC primary cultures or a non-transformed EGC line on CSCs isolated from human primary colon adenocarcinomas or colon cancer cell lines with different p53, MMR system and stemness status was determined using murine xenograft models and 3D co-culture systems. Supernatants of patient-matched human primary colon adenocarcinomas and non-adjacent healthy mucosa were used to mimic tumor versus healthy mucosa secretomes and compare their effects on EGCs.

Findings: Our data show that EGCs stimulate CSC expansion and ability to give rise to tumors via paracrine signaling. Importantly, only EGCs that were pre-activated by tumor epithelial cell-derived soluble factors increased CSC tumorigenicity. Pharmacological inhibition of PGE2 biosynthesis in EGCs or IL-1 knockdown in tumor epithelial cells prevented EGC acquisition of a pro-tumorigenic phenotype. Inhibition of PGE2 receptor EP4 and EGFR in CSCs inhibited the effects of tumor-activated EGCs.

Interpretation: Altogether, our results show that EGCs, once activated by the tumor, acquire a pro-tumorigenic phenotype and stimulate CSC-driven tumorigenesis via a PGE2/EP4/EGFR-dependent pathway.

Funding: This work was supported by grants from the French National Cancer Institute, La Ligue contre le Cancer, the 'Région des Pays de la Loire' and the UNC Lineberger Comprehensive Cancer Center.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2019.09.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945247PMC
November 2019

Glyphosate Primes Mammary Cells for Tumorigenesis by Reprogramming the Epigenome in a TET3-Dependent Manner.

Front Genet 2019 27;10:885. Epub 2019 Sep 27.

CRCINA, INSERM, Université de Nantes, Nantes, France.

The acknowledgment that pollutants might influence the epigenome raises serious concerns regarding their long-term impact on the development of chronic diseases. The herbicide glyphosate has been scrutinized for an impact on cancer incidence, but reports demonstrate the difficulty of linking estimates of exposure and response analysis. An approach to better apprehend a potential risk impact for cancer is to follow a synergistic approach, as cancer rarely occurs in response to one risk factor. The known influence of glyphosate on estrogen-regulated pathway makes it a logical target of investigation in breast cancer research. We have used nonneoplastic MCF10A cells in a repeated glyphosate exposure pattern over 21 days. Glyphosate triggered a significant reduction in DNA methylation, as shown by the level of 5-methylcytosine DNA; however, in contrast to strong demethylating agent and cancer promoter UP peptide, glyphosate-treated cells did not lead to tumor development. Whereas UP acts through a DNMT1/PCNA/UHRF1 pathway, glyphosate triggered increased activity of ten-eleven translocation (TET)3. Combining glyphosate with enhanced expression of microRNA (miR) 182-5p associated with breast cancer induced tumor development in 50% of mice. Culture of primary cells from resected tumors revealed a luminal B (ER+/PR-/HER2-) phenotype in response to glyphosate-miR182-5p exposure with sensitivity to tamoxifen and invasive and migratory potentials. Tumor development could be prevented either by specifically inhibiting miR 182-5p or by treating glyphosate-miR 182-5p-cells with dimethyloxallyl glycine, an inhibitor of TET pathway. Looking for potential epigenetic marks of TET-mediated gene regulation under glyphosate exposure, we identified and genes, the hypomethylation of which was sustained even after stopping glyphosate exposure for 6 weeks. Our findings reveal that low pressure but sustained DNA hypomethylation occurring the TET pathway primes cells for oncogenic response in the presence of another potential risk factor. These results warrant further investigation of glyphosate-mediated breast cancer risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fgene.2019.00885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777643PMC
September 2019

NKG2D Controls Natural Reactivity of Vγ9Vδ2 T Lymphocytes against Mesenchymal Glioblastoma Cells.

Clin Cancer Res 2019 12 10;25(23):7218-7228. Epub 2019 Sep 10.

CRCINA, INSERM, CNRS, Université d'Angers, Université de Nantes, Nantes, France.

Purpose: Cellular immunotherapies are currently being explored to eliminate highly invasive and chemoradioresistant glioblastoma (GBM) cells involved in rapid relapse. We recently showed that concomitant stereotactic injections of nonalloreactive allogeneic Vγ9Vδ2 T lymphocytes eradicate zoledronate-primed human GBM cells. In the present study, we investigated the spontaneous reactivity of allogeneic human Vγ9Vδ2 T lymphocytes toward primary human GBM cells, and , in the absence of any prior sensitization.

Experimental Design: Through functional and transcriptomic analyses, we extensively characterized the immunoreactivity of human Vγ9Vδ2 T lymphocytes against various primary GBM cultures directly derived from patient tumors.

Results: We evidenced that GBM cells displaying a mesenchymal signature are spontaneously eliminated by allogeneic human Vγ9Vδ2 T lymphocytes, a reactivity process being mediated by γδ T-cell receptor (TCR) and tightly regulated by cellular stress-associated NKG2D pathway. This led to the identification of highly reactive Vγ9Vδ2 T lymphocyte populations, independently of a specific TCR repertoire signature. Moreover, we finally provide evidence of immunotherapeutic efficacy , in the absence of any prior tumor cell sensitization.

Conclusions: By identifying pathways implicated in the selective natural recognition of mesenchymal GBM cell subtypes, accounting for 30% of primary diagnosed and 60% of recurrent GBM, our results pave the way for novel targeted cellular immunotherapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-0375DOI Listing
December 2019

Low-Dose Pesticide Mixture Induces Accelerated Mesenchymal Stem Cell Aging In Vitro.

Stem Cells 2019 08 17;37(8):1083-1094. Epub 2019 Apr 17.

CRCINA, INSERM U1232, Université de Nantes, Nantes, France.

The general population is chronically exposed to multiple environmental contaminants such as pesticides. We have previously demonstrated that human mesenchymal stem cells (MSCs) exposed in vitro to low doses of a mixture of seven common pesticides showed a permanent phenotype modification with a specific induction of an oxidative stress-related senescence. Pesticide mixture also induced a shift in MSC differentiation toward adipogenesis. Thus, we hypothesized that common combination of pesticides may induce a premature cellular aging of adult MSCs. Our goal was to evaluate if the prolonged exposure to pesticide mixture could accelerate aging-related markers and in particular deteriorate the immunosuppressive properties of MSCs. MSCs exposed to pesticide mixture, under long-term culture and obtained from aging donor, were compared by bulk RNA sequencing analysis. Aging, senescence, and immunomodulatory markers were compared. The protein expression of cellular aging-associated metabolic markers and immune function of MSCs were analyzed. Functional analysis of the secretome impacts on immunomodulatory properties of MSCs was realized after 21 days' exposure to pesticide mixture. The RNA sequencing analysis of MSCs exposed to pesticide showed some similarities with cells from prolonged culture, but also with the MSCs of an aged donor. Changes in the metabolic markers MDH1, GOT and SIRT3, as well as an alteration in the modulation of active T cells and modifications in cytokine production are all associated with cellular aging. A modified functional profile was found with similarities to aging process. Stem Cells 2019;37:1083-1094.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/stem.3014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850038PMC
August 2019

miR-370-3p Is a Therapeutic Tool in Anti-glioblastoma Therapy but Is Not an Intratumoral or Cell-free Circulating Biomarker.

Mol Ther Nucleic Acids 2018 Dec 13;13:642-650. Epub 2018 Sep 13.

Equipe Apoptose & Progression Tumorale, Centre de Recherche en Cancérologie et Immunologie Nantes Angers (CRCINA), INSERM U1232, Nantes, France; Faculté de Médecine, Université de Nantes, Nantes, France; LaBCT, Institut de Cancérologie de l'Ouest, Saint Herblain, France; Cancéropole Grand-Ouest, réseau Epigénétique (RepiCGO), Université de Nantes, Nantes, France; EpiSAVMEN Consortium (Région Pays de la Loire), Université de Nantes, Nantes, France; LabEX IGO, Université de Nantes, Nantes, France. Electronic address:

In the last decade, microRNAs (miRs) have been described as biomarkers and therapeutic agents. Based on this finding, our aim here is to know if (1) miRNA-370-3p can be used as a biomarker associated with a favorable survival and if (2) miRNA-370-3p can be used as a therapeutic tool that increases the efficiency of standard anti-GBM treatment. A first approach using the data available on the "Prognostic miRNA Database" indicated that the expression level of miRNA-370-3p in GBM (T-miR-370-3p) is not associated with a prognosis value for survival. A second approach quantifying the expression level of cell-free circulating miRNA-370-3p (cfc-miR-370-3p) also indicated that cfc-miR-370-3p is not associated with a prognosis value for survival. To investigate whether miR-370-3p can be used in vivo to increase the anti-GBM effect of TMZ, we then used the model of LN18-induced GBMs in mice. Our data indicated that the miRNA-370-3p/TMZ treatment was two times more efficient than the TMZ treatment for decreasing the tumor volume. In addition, our study correlated the decrease of tumor volume induced by the miRNA-370-3p/TMZ treatment with the decrease in FOXM1 and MGMT (i.e., two targets of miR-370-3p). Our data thus support the idea that miR-370-3p could be used as therapeutic tool for anti-glioblastoma therapy, but not as a biomarker.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.omtn.2018.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258828PMC
December 2018

Characterization of circulating tumor cells as a reflection of the tumor heterogeneity: myth or reality?

Drug Discov Today 2019 03 26;24(3):763-772. Epub 2018 Nov 26.

INSERM, European Associated Laboratory Sarcoma Research Unit, Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield, UK; INSERM, Institut de Cancérologie de l'Ouest, LabCT, U1232, CRCINA, Université de Nantes, Université d'Angers, Saint Herblain, France. Electronic address:

The current main goal of diagnostic medicine is to detect crucial events in 'infinitely' small samples. The key question now is how to determine whether the rare cell events isolated and characterized from these samples reliably reflect the disease and heterogeneity of the tumor. In this review, we provide a short overview of the most recent methods developed for the isolation and characterization of rare cell events in clinical practice, with a specific focus on circulating tumor cells. We discuss the biological value to studying these cells at the single cell level and how these rare cell events can reflect tumor heterogeneity. The potential biomedical applications are also critically discussed in light of precision medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.drudis.2018.11.017DOI Listing
March 2019

Dormant, quiescent, tolerant and persister cells: Four synonyms for the same target in cancer.

Biochem Pharmacol 2019 04 9;162:169-176. Epub 2018 Nov 9.

INSERM, U1232, Institut de Cancérologie de l'Ouest, Tea 9 "Apopotosis and Tumor Progression", LabCT, CRCINA, Université de Nantes, Université d'Angers, 44805 cedex, Saint Herblain, France; INSERM, European Associated Laboratory "Sarcoma Research Unit", Department of Oncology and Metabolism, Medical School, University of Sheffield, United Kingdom. Electronic address:

Although many drugs/treatments are now available for most diseases, too often, resistance to these treatments impedes complete therapeutic success. Acquired resistance is a major problem in many pathologies but it is an acute one in cancers and infections. This is probably because these diseases often require long durations of treatment, which ascribe to the selection of resistant cells. However, the actual mechanisms implicated in the selection process are still under debate. It is becoming increasingly clear that resistance is associated with the heterogeneity of cancer cells or micro-organisms and that multiple mechanisms underlie the emergence of drug-resistant subpopulations. Recently, it has been suggested that a subpopulation of drug tolerant cells present in cancer populations and called "persisters" play a major role in this resistance. Recent studies have shown that microorganisms share similar properties. Still, how persister/tolerant cells intervene in the development of resistance is not completely elucidated but seems to be related to epigenetic changes in treated cells and the capacity of persisters to modulate and/or highjack their microenvironment. Due to the complexity of this process, the input from mathematicians, as well as new methods of bioinformatics and statistics, is necessary to fully comprehend the acquisition of resistance/tolerance deriving from and leading to the heterogeneous cell populations. The present review will give a brief overview of the most recent data available on drug tolerant cells in cancers and their similarities with microorganisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bcp.2018.11.004DOI Listing
April 2019

IL-21 Increases the Reactivity of Allogeneic Human Vγ9Vδ2 T Cells Against Primary Glioblastoma Tumors.

J Immunother 2018 Jun;41(5):224-231

CRCINA, INSERM, CNRS, Université d'Angers, Université de Nantes.

Glioblastoma multiforme (GBM) remains the most frequent and deadliest primary brain tumor in adults despite aggressive treatments, because of the persistence of infiltrative and resistant tumor cells. Nonalloreactive human Vγ9Vδ2 T lymphocytes, the major peripheral γδ T-cell subset in adults, represent attractive effectors for designing immunotherapeutic strategies to track and eliminate brain tumor cells, with limited side effects. We analyzed the effects of ex vivo sensitizations of Vγ9Vδ2 T cells by IL-21, a modulating cytokine, on their cytolytic reactivity. We first showed that primary human GBM-1 cells were naturally eliminated by allogeneic Vγ9Vδ2 T lymphocytes, through a perforin/granzyme-mediated cytotoxicity. IL-21 increased both intracellular granzyme B levels and cytotoxicity of allogeneic human Vγ9Vδ2 T lymphocytes in vitro. Importantly, IL-21-enhanced cytotoxicity was rapid, which supports the development of sensitization(s) of γδ T lymphocytes before adoptive transfer, a process that avoids any deleterious effect associated with direct administrations of IL-21. Finally, we showed, for the first time, that IL-21-sensitized allogeneic Vγ9Vδ2 T cells significantly eliminated GBM tumor cells that developed in the brain after orthotopic administrations in vivo. Altogether our observations pave the way for novel efficient stereotaxic immunotherapies in GBM patients by using IL-21-sensitized allogeneic human Vγ9Vδ2 T cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CJI.0000000000000225DOI Listing
June 2018

Pharmacological targeting of apelin impairs glioblastoma growth.

Brain 2017 Nov;140(11):2939-2954

CRCINA, Inserm, Team SOAP, CNRS, Universite de Nantes, Nantes, France.

Glioblastoma are highly aggressive brain tumours that are associated with an extremely poor prognosis. Within these tumours exists a subpopulation of highly plastic self-renewing cancer cells that retain the ability to expand ex vivo as tumourspheres, induce tumour growth in mice, and have been implicated in radio- and chemo-resistance. Although their identity and fate are regulated by external cues emanating from endothelial cells, the nature of such signals remains unknown. Here, we used a mass spectrometry proteomic approach to characterize the factors released by brain endothelial cells. We report the identification of the vasoactive peptide apelin as a central regulator for endothelial-mediated maintenance of glioblastoma patient-derived cells with stem-like properties. Genetic and pharmacological targeting of apelin cognate receptor abrogates apelin- and endothelial-mediated expansion of glioblastoma patient-derived cells with stem-like properties in vitro and suppresses tumour growth in vivo. Functionally, selective competitive antagonists of apelin receptor were shown to be safe and effective in reducing tumour expansion and lengthening the survival of intracranially xenografted mice. Therefore, the apelin/apelin receptor signalling nexus may operate as a paracrine signal that sustains tumour cell expansion and progression, suggesting that apelin is a druggable factor in glioblastoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awx253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841205PMC
November 2017

HB-EGF is associated with DNA damage and Mcl-1 turnover in human glioma cell lines treated by Temozolomide.

Biochem Biophys Res Commun 2017 12 29;493(4):1377-1383. Epub 2017 Sep 29.

Team 9 "Apoptosis and Tumor Progression" CRCINA-INSERM U1232, France; Faculté de Médecine, Université de Nantes, Nantes, France; Centre Hospitalier Universitaire (CHU) de Nantes, Nantes, France. Electronic address:

Temozolomide (TMZ) is the main chemotherapeutic agent used for treating newly diagnosed Glioblastoma Multiforme (GBM), the most frequent malignant brain tumors in adults. This alkylating agent induces DNA double strand breaks (DSBs) which in turn lead to apoptosis by activating the Bcl-2 controlled mitochondrial pathway. However, GBM invariably recur as tumors become resistant to TMZ. We investigated the implication of EGFR ligands in this resistance and we found that the pro Heparin Binding Epidermal Growth Factor (proHB-EGF) expression is linked to the early response to TMZ in human glioma cell lines. However, HB-EGF does not affect apoptosis per se although its expression is associated with the degradation of Mcl-1. HB-EGF is implicated in DSBs repair as silencing of HB-EGF increased γH2AX foci half-life as well as USP9X expression, two features that could be linked to the observed effect on Mcl-1. Our data demonstrate a new role for HB-EGF in TMZ treated cell lines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2017.09.162DOI Listing
December 2017

Efficient Mitochondrial Glutamine Targeting Prevails Over Glioblastoma Metabolic Plasticity.

Clin Cancer Res 2017 Oct 18;23(20):6292-6304. Epub 2017 Jul 18.

CRCINA, INSERM, Université de Nantes, France.

Glioblastoma (GBM) is the most common and malignant form of primary human brain tumor in adults, with an average survival at diagnosis of 18 months. Metabolism is a new attractive therapeutic target in cancer; however, little is known about metabolic heterogeneity and plasticity within GBM tumors. We therefore aimed to investigate metabolic phenotyping of primary cultures in the context of molecular tumor heterogeneity to provide a proof of concept for personalized metabolic targeting of GBM. We have analyzed extensively several primary GBM cultures using transcriptomics, metabolic phenotyping assays, and mitochondrial respirometry. We found that metabolic phenotyping clearly identifies 2 clusters, GLN and GLN, mainly based on metabolic plasticity and glutamine (GLN) utilization. Inhibition of glutamine metabolism slows the and growth of GLN GBM cultures despite metabolic adaptation to nutrient availability, in particular by increasing pyruvate shuttling into mitochondria. Furthermore, phenotypic and molecular analyses show that highly proliferative GLN cultures are CD133 and display a mesenchymal signature in contrast to CD133 GLN GBM cells. Our results show that metabolic phenotyping identified an essential metabolic pathway in a GBM cell subtype, and provide a proof of concept for theranostic metabolic targeting. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-16-3102DOI Listing
October 2017

Sensitization of EGFR Wild-Type Non-Small Cell Lung Cancer Cells to EGFR-Tyrosine Kinase Inhibitor Erlotinib.

Mol Cancer Ther 2017 08 18;16(8):1634-1644. Epub 2017 May 18.

CRCINA, INSERM, Université d'Angers, Université de Nantes, Nantes, France.

The benefit of EGFR-TKI in non-small cell lung cancer has been demonstrated in mutant EGFR tumors as first-line treatment but the benefit in wild-type EGFR tumors is marginal as well as restricted to maintenance therapy in pretreated patients. This work aimed at questioning the effects of cisplatin initial treatment on the EGFR pathway in non-small cell lung cancer and the functional consequences and in animal models of patient-derived xenografts (PDX). We establish here that cisplatin pretreatment specifically sensitizes wild-type EGFR-expressing cells to erlotinib, contrary to what happens in mutant EGFR cells and with a blocking EGFR antibody, both and The sensitization entails the activation of the kinase Src upstream of EGFR, thereafter transactivating EGFR through a ligand-independent activation. We propose a combination of markers that enable to discriminate between the tumors sensitized to erlotinib or not in PDX models, which should be worth testing in patients. These markers might be useful for the selection of patients who would benefit from erlotinib as a maintenance therapy. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-17-0075DOI Listing
August 2017

Low-Dose Pesticide Mixture Induces Senescence in Normal Mesenchymal Stem Cells (MSC) and Promotes Tumorigenic Phenotype in Premalignant MSC.

Stem Cells 2017 03 23;35(3):800-811. Epub 2016 Nov 23.

Centre de Recherche en Cancérologie Nantes Angers UMR INSERM 892, CNRS 6299 - Equipe 9, Université de Nantes, Nantes, France.

Humans are chronically exposed to multiple environmental pollutants such as pesticides with no significant evidence about the safety of such poly-exposures. We exposed mesenchymal stem cells (MSC) to very low doses of mixture of seven pesticides frequently detected in food samples for 21 days in vitro. We observed a permanent phenotype modification with a specific induction of an oxidative stress-related senescence. Pesticide mixture also induced a shift in MSC differentiation towards adipogenesis but did not initiate a tumorigenic transformation. In modified MSC in which a premalignant phenotype was induced, the exposure to pesticide mixture promoted tumorigenic phenotype both in vitro and in vivo after cell implantation, in all nude mice. Our results suggest that a common combination of pesticides can induce a premature ageing of adult MSC, and as such could accelerate age-related diseases. Exposure to pesticide mixture may also promote the tumorigenic transformation in a predisposed stromal environment. Abstract Video Link: https://youtu.be/mfSVPTol-Gk Stem Cells 2017;35:800-811.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/stem.2539DOI Listing
March 2017

The phosphorylation of Metaxin 1 controls Bak activation during TNFα induced cell death.

Cell Signal 2017 01 12;30:171-178. Epub 2016 Nov 12.

Team 9 Centre de Recherche en Cancérologie Nantes-Angers, UMR INSERM 892/CNRS UMR 6299, F-44007 Nantes, France; Université de Nantes, Faculté de Médecine, 9 Quai Moncousu, 44035 Nantes Cedex 01, France; LaBCT, Institut de Cancérologie de l'Ouest-avenue Jean Monnet St Herblain, France. Electronic address:

The proapoptotic protein Bak is implicated in the execution phase of apoptosis, a cell death program. Bak is essentially mitochondrial and during early steps of apoptosis undergoes conformational changes that lead to its full membrane integration in mitochondria and the subsequent liberation of pro-apoptotic mitochondrial proteins. Little is known about the partners and mechanisms implicated in the activation of Bak. We have recently shown that Bak is incorporated into a Voltage dependent anionic channel of type 2 (VDAC2)/Metaxin 1(Mtx1)/Metaxin 2 (Mtx2) multi-protein complex in both resting and dying cells. Here, we show that, after the induction of apoptosis, Bak switches from its association with Mtx2 and VDAC2 to a closer association with Mtx1. This change of partners is under the control of a tyrosine phosphorylation of Mtx1 by c-Abl.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cellsig.2016.11.008DOI Listing
January 2017

Specific Inhibition of DNMT3A/ISGF3γ Interaction Increases the Temozolomide Efficiency to Reduce Tumor Growth.

Theranostics 2016 25;6(11):1988-1999. Epub 2016 Aug 25.

Centre de Recherche en Cancérologie Nantes-Angers, INSERM, U892, Equipe Apoptose et progression tumorale, Equipe labellisée Ligue Nationale Contre le Cancer. 8 quai moncousu, BP7021, 44007 Nantes, France.; Université de Nantes, Faculté de Médecine, Département de Recherche en Cancérologie, IFR26, F-4400, Nantes, France.; LaBCT, Institut de Cancérologie de l'Ouest, Boulevard J Monod, 44805 Nantes, Saint Herblain Cedex, France.; Member of the "Réseau Epigénétique du Canceropôle Grand-Ouest".

DNA methylation is a fundamental feature of genomes and is a candidate for pharmacological manipulation that might have important therapeutic advantage. Thus, DNA methyltransferases (DNMTs) appear to be ideal targets for drug intervention. By focusing on interactions existing between DNMT3A and DNMT3A-binding protein (D3A-BP), our work identifies the DNMT3A/ISGF3γ interaction such as a biomarker whose the presence level is associated with a poor survival prognosis and with a poor prognosis of response to the conventional chemotherapeutic treatment of glioblastoma multiforme (radiation plus temozolomide). Our data also demonstrates that the disruption of DNMT3A/ISGF3γ interactions increases the efficiency of chemotherapeutic treatment on established tumors in mice. Thus, our data opens a promising and innovative alternative to the development of specific DNMT inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/thno.9150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5039338PMC
October 2017

Stereotaxic administrations of allogeneic human Vγ9Vδ2 T cells efficiently control the development of human glioblastoma brain tumors.

Oncoimmunology 2016 Jun 30;5(6):e1168554. Epub 2016 Mar 30.

INSERM, U892, Nantes, France, Univ Nantes, Nantes, France, CNRS, UMR 6299, Nantes, France; LabEx IGO, "Immunotherapy Graft Oncology", Nantes, France.

Glioblastoma multiforme (GBM) represents the most frequent and deadliest primary brain tumor. Aggressive treatment still fails to eliminate deep brain infiltrative and highly resistant tumor cells. Human Vγ9Vδ2 T cells, the major peripheral blood γδ T cell subset, react against a wide array of tumor cells and represent attractive immune effector T cells for the design of antitumor therapies. This study aims at providing a preclinical rationale for immunotherapies in GBM based on stereotaxic administration of allogeneic human Vγ9Vδ2 T cells. The feasibility and the antitumor efficacy of stereotaxic Vγ9Vδ2 T cell injections have been investigated in orthotopic GBM mice model using selected heterogeneous and invasive primary human GBM cells. Allogeneic human Vγ9Vδ2 T cells survive and patrol for several days within the brain parenchyma following adoptive transfer and can successfully eliminate infiltrative GBM primary cells. These striking observations pave the way for optimized stereotaxic antitumor immunotherapies targeting human allogeneic Vγ9Vδ2 T cells in GBM patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/2162402X.2016.1168554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4938356PMC
June 2016

Radiation-induced PGE2 sustains human glioma cells growth and survival through EGF signaling.

Oncotarget 2015 Mar;6(9):6840-9

Centre de Recherche en Cancérologie Nantes Angers UMR INSERM 892, CNRS 6299, Université de Nantes, 44007 Nantes, France.

Glioblastoma Multiforme (GBM) is the most common brain cancer in adults. Radiotherapy (RT) is the most effective post-operative treatment for the patients even though GBM is one of the most radio-resistant tumors. Dead or dying cells within the tumor are thought to promote resistance to treatment through mechanisms that are very poorly understood. We have evaluated the role of Prostaglandin E2 (PGE2), a versatile bioactive lipid, in GBM radio-resistance. We used an in vitro approach using 3D primary cultures derived from representative GBM patients. We show that irradiated glioma cells produced and released PGE2 in important quantities independently of the induction of cell death. We demonstrate that the addition of PGE2 enhances cell survival and proliferation though its ability to trans-activate the Epithelial Growth Factor receptor (EGFR) and to activate β-catenin. Indeed, PGE2 can substitute for EGF to promote primary cultures survival and growth in vitro and the effect is likely to occur though the Prostaglandin E2 receptor EP2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4466653PMC
http://dx.doi.org/10.18632/oncotarget.3160DOI Listing
March 2015

Histone H3 phosphorylation in GBM: a new rational to guide the use of kinase inhibitors in anti-GBM therapy.

Theranostics 2015 1;5(1):12-22. Epub 2015 Jan 1.

1. Centre de Recherche en Cancérologie Nantes-Angers, INSERM, U892, Equipe Apoptose et progression tumorale, Equipe labellisée Ligue Nationale Contre le Cancer. 8 quai moncousu, BP7021, 44007 Nantes, France. ; 2. Université de Nantes, Faculté de Médecine, Département de Recherche en Cancérologie, IFR26, F-4400, Nantes, France. ; 3. LaBCT, Institut de Cancérologie de l'Ouest, Boulevard J Monod, 44805 Nantes, Saint Herblain Cedex, France. ; 4. Membre du Réseau Epigénétique du Cancéropôle Grand-Ouest.

Histones post-translational modifications (PTMs) are crucial components of diverse processes that modulate chromatin. Among the histones PTMs, the histones phosphorylation appears such crucial since it plays a significant role into DNA repair structure, transcription and chromatin compaction during cell division and apoptosis. However, little is known about the prognostic value of the histone phosphorylation in human cancer. This point could be considerate such as an important gap in anti-cancer therapy since the use of adequate kinase inhibitors could remedy to the aberrant histone phosphorylation associated with a poor prognosis factor. To remedy at this situation, we analyzed the phosphorylation level of histone H3 at the residues T3, T6, S10, S28, Y41 and T45 in a collection of 42 glioblastoma multiformes (GBM). Our data indicated that the high level of pH3T6, pH3S10 and pH3Y41 are signatures associated with a poor prognosis of overall survival (OS) of GBM treated with the "temozolomide and irradiation standard" treatment of GBM (named TMZ+Irad treatment). Our data also showed that these signatures are correlated with the high activity of kinases already described as writers of the pH3T6, pH3S10 and pH3Y41 i.e. the PKC, Aurora-B and JAK2, respectively. Finally, our analysis revealed that the use of Enzastaurin, AZD1152, and AZD1480 abrogated the high level of pH3T6, pH3S10 and pH3Y41 while increasing the sensitivity to the "temozolomide and irradiation"-induced cell death. To conclude, it appears that this work provides biomarkers for patient stratification for a therapy including kinase inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/thno.8799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4265745PMC
August 2015

Specific inhibition of DNMT1/CFP1 reduces cancer phenotypes and enhances chemotherapy effectiveness.

Epigenomics 2014 Jun;6(3):267-75

UMR 892 INSERM, 6299 CNRS, Nantes, France.

Aim: DNA methylation is a fundamental biologic process of genomes and is a candidate for pharmacological manipulation that might have important therapeutic advantages. Thus, DNA methyltransferases (DNMTs) appear to be ideal targets for drug intervention.

Materials & Methods: To develop a new generation of DNMT inhibitor, we analyzed the ability of peptides to selectively inhibit certain DNMT1-incuding complexes.

Results: Our study demonstrates that the disruption of DNMT1/CFP1-including complexes increases the efficiency of chemotherapeutic treatment on established tumors in mice.

Conclusion: Our data opens a promising and innovative alternative to the development of DNMT inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/epi.14.18DOI Listing
June 2014