0000000000589342
AUTHOR
Olivier Micheau
Chapter 16 - Carbon Nanotubes: Synthesis, Characterization, and Applications in Drug-Delivery Systems
International audience; Nanoparticles are increasingly being considered in the medical field as an effective means to deliver drugs of interest or as diagnostic biosensors. Carbon nanotubes (CNTs) are an allotropic form of carbon related to the fullerene family. Their exceptional thermal, mechanical, and electronical properties together with their tubular shape, offering a high surface area and enabling adsorption or conjugation of a wide variety of therapeutic drugs or diagnostic agents, make CNTs attractive platforms for the treatment of various diseases. This chapter reviews the emerging synthesis, characterization, and and discusses the perspectives and obstacles of these promising nano…
Regulation of the proapoptotic functions of prostate apoptosis response-4 (Par-4) by casein kinase 2 in prostate cancer cells
International audience; The proapoptotic protein, prostate apoptosis response-4 (Par-4), acts as a tumor suppressor in prostate cancer cells. The serine/threonine kinase casein kinase 2 (CK2) has a well-reported role in prostate cancer resistance to apoptotic agents or anticancer drugs. However, the mechanistic understanding on how CK2 supports survival is far from complete. In this work, we demonstrate both in rat and humans that (i) Par-4 is a new substrate of the survival kinase CK2 and (ii) phosphorylation by CK2 impairs Par-4 proapoptotic functions. We also unravel different levels of CK2-dependent regulation of Par-4 between species. In rats, the phosphorylation by CK2 at the major si…
Chemotherapy overcomes TRAIL-R4-mediated TRAIL resistance at the DISC level
International audience; TNF-related apoptosis-inducing ligand or Apo2L (Apo2L/TRAIL) is a promising anti-cancer drug owing to its ability to trigger apoptosis by binding to TRAIL-R1 or TRAIL-R2, two membrane-bound receptors that are often expressed by tumor cells. TRAIL can also bind non-functional receptors such as TRAIL-R4, but controversies still exist regarding their potential to inhibit TRAIL-induced apoptosis. We show here that TRAIL-R4, expressed either endogenously or ectopically, inhibits TRAIL-induced apoptosis. Interestingly, the combination of chemotherapeutic drugs with TRAIL restores tumor cell sensitivity to apoptosis in TRAIL-R4-expressing cells. This sensitization, which ma…
To die or not to die ? un modèle de la signalisation dichotomique de TNF-R1
1. Kurotaki N, Imaizumi K, Harada N, et al. Haplo insufficiency of NSD1 causes Sotos syndrome. Nature 2002 ; 30 : 305-6. 2. Douglas J, Hanks S, Temple K, et al. NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of Weaver syndrome but are rare in other overgroth phenotypes. Am J Hum Genet 2003 ; 27 : 132-43. 3. Rio M, Clech L, Amiel J, et al. Spectrum of NSD1 mutations in Sotos and Weaver syndromes. J Med Genet 2003 ; 40 : 436-40. 4. Imaizumi K, Kimura J, Matsuo M, et al. Sotos syndrome associated with a de novo balanced reciprocal translocation t(5 ;8)(q35 ;q24.1). Am J Hum Genet 2002 ; 107 : 58-60. 5. Opitz JM, Weaver DW, Reynolds JF. The syndrome of Sotos and We…
Marine Actinomycetes-Derived Secondary Metabolites Overcome TRAIL-Resistance via the Intrinsic Pathway through Downregulation of Survivin and XIAP
Resistance of cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis represents the major hurdle to the clinical use of TRAIL or its derivatives. The discovery and development of lead compounds able to sensitize tumor cells to TRAIL-induced cell death is thus likely to overcome this limitation. We recently reported that marine actinomycetes&rsquo
Colony-stimulating factor-1-induced oscillations in phosphatidylinositol-3 kinase/AKT are required for caspase activation in monocytes undergoing differentiation into macrophages.
Abstract The differentiation of human peripheral blood monocytes into resident macrophages is driven by colony-stimulating factor-1 (CSF-1), which upon interaction with CSF-1 receptor (CSF-1R) induces within minutes the phosphorylation of its cytoplasmic tyrosine residues and the activation of multiple signaling complexes. Caspase-8 and -3 are activated at day 2 to 3 and contribute to macrophage differentiation, for example, through cleavage of nucleophosmin. Here, we show that the phosphatidylinositol-3 kinase and the downstream serine/threonine kinase AKT connect CSF-1R activation to caspase-8 cleavage. Most importantly, we demonstrate that successive waves of AKT activation with increasi…
TRAIL in cancer therapy: present and future challenges.
International audience; Since its identification in 1995, TNF-related apoptosis-inducing ligand (TRAIL) has sparked growing interest in oncology due to its reported ability to selectively trigger cancer cell death. In contrast to other members of the TNF superfamily, TRAIL administration in vivo is safe. The relative absence of toxic side effects of this naturally occurring cytokine, in addition to its antitumoural properties, has led to its preclinical evaluation. However, despite intensive investigations, little is known in regards to the mechanisms underlying TRAIL selectivity or efficiency. An appropriate understanding of its physiological relevance, and of the mechanisms controlling ca…
dsRNA induces apoptosis through an atypical death complex associating TLR3 to caspase-8
Toll-like receptor 3 (TLR3) is a pattern-recognition receptor known to initiate an innate immune response when stimulated by double-stranded RNA (dsRNA). Components of TLR3 signaling, including TIR domain-containing adapter inducing IFN-α (TRIF), have been demonstrated to contribute to dsRNA-induced cell death through caspase-8 and receptor interacting protein (RIP)1 in various human cancer cells. We provide here a detailed analysis of the caspase-8 activating machinery triggered in response to Poly(I:C) dsRNA. Engagement of TLR3 by dsRNA in both type I and type II lung cancer cells induces the formation of an atypical caspase-8-containing complex that is devoid of classical death receptors…
Death receptors as targets in cancer
Anti-tumour therapies based on the use PARAs (pro-apoptotic receptor agonists), including TRAIL (TNF-Related Apoptosis inducing Ligand) or monoclonal antibodies targeting TRAIL-R1 or TRAIL-R2, have been disappointing so far, despite clear evidence of clinical activity and lack of adverse events for the vast majority of these compounds, whether combined or not with conventional or targeted anti-cancer therapies. This brief review aims at discussing the possible reasons for the lack of apparent success of these therapeutic approaches and at providing hints in order to rationally design optimal protocols based on our current understanding of TRAIL signalling regulation or resistance for future…
Caspase-8 prevents sustained activation of NF-kappaB in monocytes undergoing macrophagic differentiation.
Abstract Caspases have demonstrated several nonapoptotic functions including a role in the differentiation of specific cell types. Here, we show that caspase-8 is the upstream enzyme in the proteolytic caspase cascade whose activation is required for the differentiation of peripheral-blood monocytes into macrophages. On macrophage colony-stimulating factor (M-CSF) exposure, caspase-8 associates with the adaptor protein Fas-associated death domain (FADD), the serine/threonine kinase receptor-interacting protein 1 (RIP1) and the long isoform of FLICE-inhibitory protein FLIP. Overexpression of FADD accelerates the differentiation process that does not involve any death receptor. Active caspase…
Thiocolchicoside a semi-synthetic derivative of the Glory Lily: a new weapon to fight metastatic bone resorption?
Metastatic bone disease is a serious clinical complication for the treatment of patients with advanced cancer, but few therapeutic options are currently available. Bisphosphonates are an established standard care for these patients, but new treatments are now emerging, including the use of monoclonal antibodies targeting the RANK ligand. In this issue of the BJP, Reuter et al. provide evidence that thiocolchicoside, a semi-synthetic derivative of the naturally occurring colchicoside, extracted from the seeds of Gloriosa superba (Liliaceae), prevented osteoclactogenesis by suppressing RANK ligand-mediated NF-κB activation. Thiolcolchicoside may thus represent an attractive therapeutic option…
Carbon Nanotubes
Abstract Nanoparticles are increasingly being considered in the medical field as an effective means to deliver drugs of interest or as diagnostic biosensors. Carbon nanotubes (CNTs) are an allotropic form of carbon related to the fullerene family. Their exceptional thermal, mechanical, and electronical properties together with their tubular shape, offering a high surface area and enabling adsorption or conjugation of a wide variety of therapeutic drugs or diagnostic agents, make CNTs attractive platforms for the treatment of various diseases. This chapter reviews the emerging synthesis, characterization, and medical applications of CNTs and discusses the perspectives and obstacles of these …
TRAIL-R4 promotes tumor growth and resistance to apoptosis in cervical carcinoma HeLa cells through AKT.
International audience; BACKGROUND: TRAIL/Apo2L is a pro-apoptotic ligand of the TNF family that engages the apoptotic machinery through two pro-apoptotic receptors, TRAIL-R1 and TRAIL-R2. This cell death program is tightly controlled by two antagonistic receptors, TRAIL-R3 and TRAIL-R4, both devoid of a functional death domain, an intracellular region of the receptor, required for the recruitment and the activation of initiator caspases. Upon TRAIL-binding, TRAIL-R4 forms a heteromeric complex with the agonistic receptor TRAIL-R2 leading to reduced caspase-8 activation and apoptosis. METHODOLOGY/PRINCIPAL FINDINGS: We provide evidence that TRAIL-R4 can also exhibit, in a ligand independent…
TRAIL–NP hybrids for cancer therapy: a review
IF 7.367; International audience; Cancer is a worldwide health problem. It is now considered as a leading cause of morbidity and mortality in developed countries. In the last few decades, considerable progress has been made in anti-cancer therapies, allowing the cure of patients suffering from this disease, or at least helping to prolong their lives. Several cancers, such as those of the lung and pancreas, are still devastating in the absence of therapeutic options. In the early 90s, TRAIL (Tumor Necrosis Factor-related apoptosis-inducing ligand), a cytokine belonging to the TNF superfamily, attracted major interest in oncology owing to its selective anti-tumor properties. Clinical trials u…
Small heat shock proteins and the cytoskeleton: an essential interplay for cell integrity?
Abstract The cytoskeleton is a highly complex network of three major intracellular filaments, microfilaments (MFs), microtubules (MTs) and intermediate filaments (IFs). This network plays a key role in the control of cell shape, division, functions and interactions in animal organs and tissues. Dysregulation of the network can contribute to numerous human diseases. Although small HSPs (sHSPs) and in particular HSP27 (HSPB1) or αB-crystallin (HSPB5) display a wide range of cellular properties, they are mostly known for their ability to protect cells under stress conditions. Mutations in some sHSPs have been found to affect their ability to interact with cytoskeleton proteins, leading to IF a…
Inhibition of HSP27 blocks fibrosis development and EMT features by promoting Snail degradation
Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by myofibroblast proliferation. Transition of epithelial/mesothelial cells into myofibroblasts [epithelial-to-mesenchymal transition (EMT)] occurs under the influence of transforming growth factor (TGF)-β1, with Snail being a major transcription factor. We study here the role of the heat-shock protein HSP27 in fibrogenesis and EMT. In vitro, we have up- and down-modulated HSP27 expression in mesothelial and epithelial cell lines and studied the expression of different EMT markers induced by TGF-β1. In vivo, we inhibited HSP27 with the antisense oligonucleotide OGX-427 (in phase II clinical trials as anticancer agent)…
TRAIL Triggers CRAC-Dependent Calcium Influx and Apoptosis through the Recruitment of Autophagy Proteins to Death-Inducing Signaling Complex
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively kills various cancer cell types, but also leads to the activation of signaling pathways that favor resistance to cell death. Here, we investigated the as yet unknown roles of calcium signaling and autophagy regulatory proteins during TRAIL-induced cell death in leukemia cells. Taking advantage of the Gene Expression Profiling Interactive Analysis (GEPIA) project, we first found that leukemia patients present a unique TRAIL receptor gene expression pattern that may reflect their resistance to TRAIL. The exposure of NB4 acute promyelocytic leukemia cells to TRAIL induces intracellular Ca2+ influx through a calcium rel…
Death receptors as targets in cancer
Anti-tumour therapies based on the use PARAs (pro-apoptotic receptor agonists), including TRAIL (TNF-Related Apoptosis inducing Ligand) or monoclonal antibodies targeting TRAIL-R1 or TRAIL-R2, have been disappointing so far, despite clear evidence of clinical activity and lack of adverse events for the vast majority of these compounds, whether combined or not with conventional or targeted anti-cancer therapies. This brief review aims at discussing the possible reasons for the lack of apparent success of these therapeutic approaches and at providing hints in order to rationally design optimal protocols based on our current understanding of TRAIL signalling regulation or resistance for future…