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Cell type-dependent ROS and mitophagy response leads to apoptosis or necroptosis in neuroblastoma
Radogna, F,Cerella, C,Gaigneaux, A,Christov, C,Dicato, M,Diederich, M Macmillan Publishers Limited 2016 Oncogene Vol.35 No.29
<P>A limiting factor in the therapeutic outcome of children with high-risk neuroblastoma is the intrinsic and acquired resistance to common chemotherapeutic treatments. Here we investigated the molecular mechanisms by which the hemisynthetic cardiac glycoside UNBS1450 overcomes this limitation and induces differential cell death modalities in both neuroblastic and stromal neuroblastoma through stimulation of a cell-type-specific autophagic response eventually leading to apoptosis or necroptosis. In neuroblastic SH-SY5Y cells, we observed a time-dependent production of reactive oxygen species that affects lysosomal integrity inducing lysosome-associated membrane protein 2 degradation and cathepsin B and L activation. Subsequent mitochondrial membrane depolarization and accumulation of mitochondria in phagophores occurred after 8h of UNBS1450 treatment. Results were confirmed by mitochondrial mass analysis, electron microscopy and co-localization of mitochondria with GFP-LC3, suggesting the impaired clearance of damaged mitochondria. Thus, a stress-induced defective autophagic flux and the subsequent lack of clearance of damaged mitochondria sensitized SH-SY5Y cells to UNBS1450-induced apoptosis. Inhibition of autophagy with small inhibitory RNAs against ATG5, ATG7 and Beclin-1 protected SH-SY5Y cells against the cytotoxic effect of UNBS1450 by inhibiting apoptosis. In contrast, autophagy progression towards the catabolic state was observed in stromal SK-N-AS cells: here reactive oxygen species (ROS) generation remained undetectable preserving intact lysosomes and engulfing damaged mitochondria after UNBS1450 treatment. Moreover, autophagy inhibition determined sensitization of SK-N-AS to apoptosis. We identified efficient mitophagy as the key mechanism leading to failure of activation of the apoptotic pathway that increased resistance of SK-N-AS to UNBS1450, triggering rather necroptosis at higher doses. Altogether we characterize here the differential modulation of ROS and mitophagy as a main determinant of neuroblastoma resistance with potential relevance for personalized anticancer therapeutic approaches.</P>
Trecul, A.,Morceau, F.,Gaigneaux, A.,Orsini, M.,Chateauvieux, S.,Grandjenette, C.,Dicato, M.,Diederich, M. Elsevier Science Ireland 2013 Cancer letters Vol.340 No.1
Constitutive activity of kinases has been reported in many types of cancers, so that inhibition of ''onco-kinases'' became a validated anti-cancer strategy. We found that the polyphenol 13c, a tri-vanillate derivative, inhibited kinase phosphorylation in leukemia cells. P-JAK2, P-Src and P-PI3Kp85 inhibition occurred independently of phosphatase involvement in JAK2V617F expressing HEL cells while 13c inhibited Bcr-Abl expression without inhibition of phosphorylation in chronic myelogenous leukemia cell lines (K562, MEG-01). In correlation with kinase inhibition, 13c abolished constitutive P-STAT3/P-STAT5 expression, down-regulated Mcl-1 and c-Myc gene expression and induced apoptosis. Altogether, polyphenol 13c displays potential antitumor activities by affecting onco-kinases and STAT activities.
Long and Short Non-Coding RNAs as Regulators of Hematopoietic Differentiation
Morceau, Franck,Chateauvieux, Sé,bastien,Gaigneaux, Anthoula,Dicato, Mario,Diederich, Marc Molecular Diversity Preservation International (MD 2013 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.14 No.7
<P>Genomic analyses estimated that the proportion of the genome encoding proteins corresponds to approximately 1.5%, while at least 66% are transcribed, suggesting that many non-coding DNA-regions generate non-coding RNAs (ncRNAs). The relevance of these ncRNAs in biological, physiological as well as in pathological processes increased over the last two decades with the understanding of their implication in complex regulatory networks. This review particularly focuses on the involvement of two large families of ncRNAs, namely microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in the regulation of hematopoiesis. To date, miRNAs have been widely studied, leading to a wealth of data about processing, regulation and mechanisms of action and more specifically, their involvement in hematopoietic differentiation. Notably, the interaction of miRNAs with the regulatory network of transcription factors is well documented whereas roles, regulation and mechanisms of lncRNAs remain largely unexplored in hematopoiesis; this review gathers current data about lncRNAs as well as both potential and confirmed roles in normal and pathological hematopoiesis.</P>
Yagdi Efe, Esma,Mazumder, Aloran,Lee, Jin-Young,Gaigneaux, Anthoula,Radogna, Flavia,Nasim, Muhammad Jawad,Christov, Christo,Jacob, Claus,Kim, Kyu-Won,Dicato, Mario,Chaimbault, Patrick,Cerella, Claudia Elsevier 2017 Cancer letters Vol.410 No.-
<P><B>Abstract</B></P> <P>Polysulfanes show chemopreventive effects against gastrointestinal tumors. We identified diallyl tetrasulfide and its derivative, dibenzyl tetrasulfide (DBTTS), to be mitotic inhibitors and apoptosis inducers. Here, we translate their application in colorectal cancer (CRC). MALDI-TOF-MS analysis identified both compounds as reversible tubulin binders, validated by <I>in cellulo</I> α-tubulin degradation. BRAF(V600E)-mutated HT-29 cells were resistant to DBTTS, as evidenced by mitotic arrest for 48 h prior to apoptosis induction compared to KRAS(G12V)-mutated SW480/620 cells, which committed to death earlier. The prolonged mitotic block correlated with autophagy impairment and p62 protein accumulation in HT-29 but not in SW480/620 cells, whereas siRNA-mediated p62 inhibition sensitized HT-29 cells to death. <I>In silico</I> analysis with 484 colorectal cancer patients associated higher p62 expression and reduced autophagic flux with greater overall survival. Accordingly, we hypothesized that DBTTS targets CRC survival/death through autophagy interference in cell types with differential autophagic capacities. We confirmed the therapeutic potential of DBTTS by the inhibition of spheroid and colony formation capacities in CRC cells, as well as in HT-29 zebrafish xenografts <I>in vivo</I>.</P>
De Bosscher, Karolien,Beck, Ilse M.,Dejager, Lien,Bougarne, Nadia,Gaigneaux, Anthoula,Chateauvieux, Sé,bastien,Ratman, Dariusz,Bracke, Marc,Tavernier, Jan,Vanden Berghe, Wim,Libert, Claude,Diede Springer Basel 2014 Cellular and molecular life sciences Vol.71 No.1
<P>Glucocorticoids (GCs) block inflammation via interference of the liganded glucocorticoid receptor (GR) with the activity of pro-inflammatory transcription factors NF-κB and AP-1, a mechanism known as transrepression. This mechanism is believed to involve the activity of GR monomers. Here, we explored how the GR monomer-favoring Compound A (CpdA) affects AP-1 activation and activity. Our results demonstrate that non-steroidal CpdA, unlike classic steroidal GCs, blocks NF-κB- but not AP-1-driven gene expression. CpdA rather sustains AP-1-driven gene expression, a result which could mechanistically be explained by the failure of CpdA to block upstream JNK kinase activation and concomitantly also phosphorylation of c-Jun. In concordance and in contrast to DEX, CpdA maintained the expression of the activated AP-1 target gene <I>c</I>-<I>jun</I>, as well as the production of the c-Jun protein. As for the underlying mechanism, GR is a necessary intermediate in the CpdA-mediated gene expression of AP-1-regulated genes, but seems to be superfluous to CpdA-mediated JNK phosphorylation prolongation. The latter phenomenon concurs with the inability of CpdA to stimulate DUSP1 gene expression. ChIP analysis demonstrates that DEX-activated GR, but not CpdA-activated GR, is recruited to AP-1-driven promoters. Furthermore, in mice we observed that CpdA instigates a strong enhancement of TNF-induced AP-1-driven gene expression. Finally, we demonstrate that this phenomenon coincides with an increased sensitivity towards TNF lethality, and implicate again a role for JNK2. In conclusion, our data support the hypothesis that a ligand-induced differential conformation of GR yields a different transcription factor cross-talk profile.</P><P><B>Electronic supplementary material</B></P><P>The online version of this article (doi:10.1007/s00018-013-1367-4) contains supplementary material, which is available to authorized users.</P>
Lee, Jin-Young,Talhi, Oualid,Jang, Dongman,Cerella, Claudia,Gaigneaux, Anthoula,Kim, Kyu-Won,Lee, Jung Weon,Dicato, Mario,Bachari, Khaldoun,Han, Byung Woo,Silva, Artur M.S.,Orlikova, Barbora,Diederich Elsevier 2018 Cancer letters Vol.416 No.-
<P><B>Abstract</B></P> <P>Coumarins are natural compounds with antioxidant, anti-inflammatory and anti-cancer potential known to modulate inflammatory pathways. Here, non-toxic biscoumarin OT52 strongly inhibited proliferation of non-small cell lung cancer cells with KRAS mutations, inhibited stem-like characteristics by reducing aldehyde dehydrogenase expression and abrogated spheroid formation capacity. This cytostatic effect was characterized by cell cycle arrest and onset of senescence concomitant with endoplasmic reticulum and Golgi stress, leading to metabolic alterations. Mechanistically, this cellular response was associated with the novel capacity of biscoumarin OT52 to inhibit STAT3 transactivation and expression of its target genes linked to proliferation. These results were validated by computational docking of OT52 to the STAT3 DNA-binding domain. Combination treatments of OT52 with subtoxic concentrations of Bcl-xL and Mcl-1-targeting BH3 protein inhibitors triggered synergistic immunogenic cell death validated in colony formation assays as well as <I>in vivo</I> by zebrafish xenografts.</P>
Protein Kinase and HDAC Inhibitors from the Endophytic Fungus <i>Epicoccum nigrum</i>
El Amrani, Mustapha,Lai, Daowan,Debbab, Abdessamad,Aly, Amal H.,Siems, Karsten,Seidel, Carole,Schnekenburger, Michael,Gaigneaux, Anthoula,Diederich, Marc,Feger, Daniel,Lin, Wenhan,Proksch, Peter American Chemical Society and American Society of 2014 Journal of natural products Vol.77 No.1
<P>A chemical investigation of the endophytic fungus <I>Epicoccum nigrum</I> isolated from leaves of <I>Mentha suaveolens</I> collected in Morocco resulted in the isolation of five new polyketides, epicocconigrones A and B (<B>1</B> and <B>2</B>), 3-methoxyepicoccone B (<B>3</B>), 3-methoxyepicoccone (<B>4</B>), and 2,3,4-trihydroxy-6-(methoxymethyl)-5-methylbenzaldehyde (<B>5</B>), together with five known compounds (<B>6</B>–<B>10</B>). The structures of the new compounds were unambiguously determined by extensive analysis of the 1D and 2D NMR and mass spectroscopic data. Compounds <B>1</B> and <B>10</B> showed potent inhibition of at least 15 protein kinases with IC<SUB>50</SUB> values ranging from 0.07 to 9.00 μM. Moreover, compounds <B>1</B> and <B>10</B> inhibited histone deacetylase (HDAC) activities with IC<SUB>50</SUB> values of 9.8 and 14.2 μM, respectively. A preliminary structure–activity relationship is discussed. Interestingly, compounds <B>1</B> and <B>10</B> exert mainly cytostatic effects in human lymphoma RAJI and U-937 cell lines.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jnprdf/2014/jnprdf.2014.77.issue-1/np4005745/production/images/medium/np-2013-005745_0008.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/np4005745'>ACS Electronic Supporting Info</A></P>
Mazumder, Aloran,Lee, Jin-Young,Talhi, Oualid,Cerella, Claudia,Chateauvieux, Sé,bastien,Gaigneaux, Anthoula,Hong, Che Ry,Kang, Hyoung Jin,Lee, Youngjo,Kim, Kyu-Won,Kim, Dong-Wook,Shin, Hee-Young Elsevier 2018 Cancer letters Vol.438 No.-
<P><B>Abstract</B></P> <P>We synthetized and investigated the anti-leukemic potential of the novel cytostatic bis(4-hydroxycoumarin) derivative OT-55 which complied with the Lipinski's rule of 5 and induced differential toxicity in various chronic myeloid leukemia (CML) cell models. OT-55 triggered ER stress leading to canonical, caspase-dependent apoptosis and release of danger associated molecular patterns. Consequently, OT-55 promoted phagocytosis of OT-55-treated CML cells by both murine and human monocyte-derived macrophages. Moreover, OT-55 inhibited tumor necrosis factor α-induced activation of nuclear factor-кB and produced synergistic effects when used in combination with imatinib to inhibit colony formation <I>in vitro</I> and Bcr-Abl<SUP>+</SUP> patient blast xenograft growth in zebrafish. Furthermore, OT-55 synergized with omacetaxine in imatinib-resistant KBM-5 R cells to inhibit the expression of Mcl-1, triggering apoptosis. In imatinib-resistant K562 R cells, OT-55 triggered necrosis and blocked tumor formation in zebrafish in combination with omacetaxine.</P> <P><B>Highlights</B></P> <P> <UL> <LI> OT-55 inhibits cell proliferation and viability in CML. </LI> <LI> OT-55 induces ER stress, ecto-CRT, ecto-ERp57, ATP and HMGB1 elease leading to immunogenic cell death. </LI> <LI> OT-55-treated CML cells are phagocytosed by macrophages. </LI> <LI> OT-55 synergizes with imatinib in CML. </LI> <LI> OT-55 synergizes with Synribo in Bcr-Abl mutated CML. </LI> </UL> </P>