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Cancer cells show particular features such as resistance to apoptosis and metastasis ability. Moreover, it has been reported that cancer cell exhibit a poor antioxidant status, high rates of glycolysis and a capacity to accumulate vitamin C. Regardless to these features, we developed a new and original anticancer approach by exposing K-562 cells to an oxidative stress by the association of vitamin C and vitamin K3.
The chaperone protein Hsp90 plays a major role in K-562 cell survival by stabilizing the oncogenic protein Bcr-Abl under a complex that renders its protein tyrosine kinase in a high activity. This complex is requiring ATP for an optimal stabilization. Since CK3 depletes the intracellular levels of ATP, the aim of this work was to study the mechanisms by which the association vitamin C/vitamin K3 induces the degradation of the oncogenic protein Bcr-Abl in K-562 cells.
Our results show a loss in the phosphorylation levels of Bcr-Abl as well as in several proteins that belong to its signaling pathway. Such a loss activated proteins that belong is mainly explained by the degradation of the Bcr-Abl protein induced by CK3. This protein degradation seems to be the consequence of Hsp90 protein cleavage which destabilizes the client protein (Bcr-Abl). The cleavage of Hsp90 is independent of ATP depletion and is not involving a proteasome activity. Moreover, the inhibition of autophagy seems to protect against the effects of CK3. Finally, by modulating the activity of CK3 through the addition of either an antioxidant molecule such as N-acetylcystein (a GSH precursor), or a catalase inhibitor (3-aminotriazole), and a H2O2-generating system (glucose/Glox), we concluded about a major role of oxidative stress and H2O2 as the main ROS (Reactive Oxygen Species) involved in Hsp90 cleavage, Bcr-Abl degradation and K-562 cell death Les cellules cancéreuses possèdent de nombreuses caractéristiques dont notamment une capacité de résistance à l’apoptose et d’envahissement d’autres tissus. De plus, elles sont défcientes en enzymes antioxydantes, leur métabolisme glycolytique est très élevé et en conséquence de la surexpression des transporteurs au glucose, elles ont la particularité d’accumuler la vitamine C. C’est pourquoi nous avons développé au laboratoire une nouvelle stratégie anticancéreuse qui consiste à générer au sein des cellules malignes un stress oxydatif à partir de la combinaison entre la vitamine C et la ménadione, ou vitamine K3.
La protéine chaperonne joue un rôle important dans la survie des cellules K-562 en interagissant avec l’oncoprotéine Bcr-Abl de manière à former un complexe. Cette interaction stabilise Bcr-Abl et rend son activité tyrosine kinase élevée. Ce complexe requiert de l’ATP pour une stabilisation optimale. Etant donné que CK3 entraîne une déplétion des taux intracellulaires en ATP, le but de ce travail est d’étudier les mécanismes par lesquels l’association des vitamines C et K3 induit une dégradation de la protéine oncogénique Bcr-Abl dans des cellules K-562 de leucémie myéloïde chronique.
Nos résultats montrent une perte de la phosphorylation de Bcr-Abl ainsi qu’une diminution de sa signalisation. Celles-ci sont le résultat d’une dégradation de la protéine Bcr-Abl induite par CK3. Cette dégradation est rendue possible suite au fait que nous avons observé un clivage de la protéine Hsp90, responsable de la stabilité de Bcr-Abl. Ce clivage est indépendant de la chute d’ATP également provoquée par la combinaison vitaminique et il n’est pas réalisé par le protéasome. D’autre part, l’inhibition de l’autophagie semble protéger contre les effets de CK3. Le rôle majeur du stress oxydatif a également été confirmé sur ces effets induits par CK3 en modulant son activité via l’addition de différents antioxydants comme la N-acétylcystéine (un précurseur du glutathion), un inhibiteur de la catalase (le 3-aminotriazole) et via un système générateur d’H2O2 (Glucose/Glox). Nous avons conclu que le peroxyde d’hydrogène est le principal agent oxydant impliqué dans le clivage de Hsp90, la dégradation de Bcr-Abl et la mort des cellules K-562

HSP90 Heat-Shock Proteins --- Oxidative Stress --- Fusion Proteins, bcr-abl --- Leukemia, Myeloid, Chronic --- Cell Death

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Previous studies demonstrated a synergistic cytotoxic effect by ascorbate-menadione on various types of cancer cells. When used in combination, ascorbate and menadione are entering a redox cycle leading to hydrogen peroxide production, which seems to be the basis of this cytotoxicity. Recent studies suggest that oxidative stress generated by ascorbate/menadione affects Hsp90 leading to the degradation of some critical proteins and cell death. Moreover, this association leads to the appearance of an additional Hsp90 protein band of about 70 kDa, suggesting Hsp90 cleavage,in the K562 leukemia myelogenous chronic cells.ln this study, we first confirmed the presence of the additional Hsp90 protein band induced by ascorbate/menadione in murine hepatocarcinoma cells (Transplantable liver tumor).Secondly, by using two modulators of oxidative stress, N-acetylcysteine and 3-aminotriazole, we showed the implication of oxidative stress in the Hsp90 cleavage.Thirdly, by using two calcium chelating agents, namely Bapta-AM and EGTA, we showed that intracellular calcium may be implicated in this cleavage.Finally, by using some metabolic inhibitors of Hsp90, we founded that both the cleavage of Hsp90 and the cytotoxicity induced by ascorbate/menadione are not necessarily correlated. That means that Hsp90 cleavage is not the only expianation of cell death. As conclusion, given the key role played by Hsp90 in cancer cells stabilizing mutated proteins critical for their survival, we would like to propose ascorbate/menadione as a new non toxic adjuvant anticancer therapy, without presenting any supplementary risk for the patients.

Oxidative Stress --- HSP90 Heat-Shock Proteins --- Liver Neoplasms, Experimental --- Vitamin K 3 --- Ascorbic Acid --- Mice

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Immunohistochemistry (IHC) is an ancillary method, widely used in pathologists’ practice, that allows identifying diagnostic and prognostic/predictive of therapeutic response protein markers on tissue samples by the use of specific monoclonal antibodies and chromogenic substances that guarantee the visualization of an antibody–antigene binding complex under a light microscope [1]. Coon et al., in 1941 [2], first introduced the use of fluorochrome-conjugated antibodies in clinical practice. Since then, IHC has gone from being a useful tool for identifying the differentiation line of otherwise undifferentiated cells to a technique capable of providing not only diagnostic but also prognostic and predictive indications of responses to specific therapeutic options [1,3]. The abovementioned peculiarities have made IHC one of the most used ancillary methods in the histopathological approach to human neoplastic and non-neoplastic diseases [3-5]. This Special Issue contains 11 accepted papers that provide readers with a comprehensive update on current and future applications of IHC in medical practice.

training exercise --- NGAL --- VDR --- kidney --- heart --- immunohistochemistry --- ABCB5 --- uveal melanoma --- prognosis --- metastasis --- pericardium --- cytokeratin --- c-kit --- PDGFR --- initial lymphatics --- macroH2A --- prognostic factor --- SLC22A12 --- URAT1 --- hypouricemia --- uric acid transporters --- excretion fraction of uric acid --- Hsp27 --- Hsp60 --- Hsp70 --- Hsp90 --- molecular chaperone --- chaperonopathies --- thyroid --- follicular adenoma --- follicular carcinoma --- differential diagnosis --- carcinogenesis --- matrix metalloproteinases --- temporomandibular joint disorder --- temporomandibular joint --- DEN --- liver --- inflammation --- ultra-structural changes --- oxidative stress --- EGCG --- Vitamin D --- prostate cancer --- urinary tract malformations --- megacystis --- enteric nervous system --- outcome and prognosis --- WT1 --- human embryonal/fetal tissues --- neoplastic tissue --- n/a

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Zika virus (ZIKV), one of the flavivirus family members transmitted by mosquitos, was declared a Public Health Emergency of International Concern by the WHO in February 2016 because of clusters of newborn microcephaly cases and other neurological disorders in Brazil. Most ZIKV infections result in a self-limited flu-like febrile disease, however, if contracted during pregnancy, the virus can also infect fetuses and cause a spectrum of birth defects known as congenital Zika syndrome. To date, no vaccines or antiviral drugs are licensed for ZIKV, and the virus has spread and become endemic to many tropical and sub-tropical countries. Included in this book are thirteen reports addressing diverse aspects of ZIKV–host interactions. These studies range from basic science to clinical research. It is expected that findings from these studies will contribute to a better understanding of the host cells interacting with ZIKV, and may serve as the basis for new diagnostics, antiviral therapies, and vaccine design.

Research & information: general --- Biology, life sciences --- Zika virus --- peroxisomes --- innate immune response --- interferon --- astrocytes --- fetal brain --- zika virus --- flaviviruses --- T cells --- host-pathogen interactions --- flavivirus --- tight junctions --- claudins --- ZO-1 --- blood-placental barrier --- placenta --- apoptosis --- viral replication --- Bcl-2 protein family --- ZIKV --- virus host interactions --- pathogenesis --- MR766 --- guinea pig --- subcutaneous --- vaginal --- sexual transmission --- virus transmission --- envelope protein --- glycosylation --- fusion loop --- viral fusion --- cell entry --- NS5 protein --- nuclear localization --- inflammation --- innate immunity --- extracellular vesicles --- cellular communication --- C6/36 cells --- human monocytes --- endothelial vascular cells --- protein–protein interaction --- non-structural viral proteins --- network --- JAK/STAT --- cytokine --- West Nile virus --- HSP90 --- NS5 --- virus–host interactions --- anti-viral signaling --- immune response --- inflammatory mediator --- Sertoli cells --- Leydig cells --- ZIKA virus --- arboviruses --- infertility --- IFN --- RIG-I --- MDA5 --- IFNAR1 --- zika --- host --- cell death --- peroxisome --- mosquito --- tight junction

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Zika virus (ZIKV), one of the flavivirus family members transmitted by mosquitos, was declared a Public Health Emergency of International Concern by the WHO in February 2016 because of clusters of newborn microcephaly cases and other neurological disorders in Brazil. Most ZIKV infections result in a self-limited flu-like febrile disease, however, if contracted during pregnancy, the virus can also infect fetuses and cause a spectrum of birth defects known as congenital Zika syndrome. To date, no vaccines or antiviral drugs are licensed for ZIKV, and the virus has spread and become endemic to many tropical and sub-tropical countries. Included in this book are thirteen reports addressing diverse aspects of ZIKV–host interactions. These studies range from basic science to clinical research. It is expected that findings from these studies will contribute to a better understanding of the host cells interacting with ZIKV, and may serve as the basis for new diagnostics, antiviral therapies, and vaccine design.

Research & information: general --- Biology, life sciences --- Zika virus --- peroxisomes --- innate immune response --- interferon --- astrocytes --- fetal brain --- zika virus --- flaviviruses --- T cells --- host-pathogen interactions --- flavivirus --- tight junctions --- claudins --- ZO-1 --- blood-placental barrier --- placenta --- apoptosis --- viral replication --- Bcl-2 protein family --- ZIKV --- virus host interactions --- pathogenesis --- MR766 --- guinea pig --- subcutaneous --- vaginal --- sexual transmission --- virus transmission --- envelope protein --- glycosylation --- fusion loop --- viral fusion --- cell entry --- NS5 protein --- nuclear localization --- inflammation --- innate immunity --- extracellular vesicles --- cellular communication --- C6/36 cells --- human monocytes --- endothelial vascular cells --- protein–protein interaction --- non-structural viral proteins --- network --- JAK/STAT --- cytokine --- West Nile virus --- HSP90 --- NS5 --- virus–host interactions --- anti-viral signaling --- immune response --- inflammatory mediator --- Sertoli cells --- Leydig cells --- ZIKA virus --- arboviruses --- infertility --- IFN --- RIG-I --- MDA5 --- IFNAR1 --- zika --- host --- cell death --- peroxisome --- mosquito --- tight junction