Search results for "P3"

Pharmacological targeting of the novel β-catenin chromatin-associated kinase p38α in colorectal cancer stem cell tumorspheres and organoids

2021

AbstractThe prognosis of locally advanced colorectal cancer (CRC) is currently unsatisfactory. This is mainly due to drug resistance, recurrence, and subsequent metastatic dissemination, which are sustained by the cancer stem cell (CSC) population. The main driver of the CSC gene expression program is Wnt signaling, and previous reports indicate that Wnt3a can activate p38 MAPK. Besides, p38 was shown to feed into the canonical Wnt/β-catenin pathway. Here we show that patient-derived locally advanced CRC stem cells (CRC-SCs) are characterized by increased expression of p38α and are “addicted” to its kinase activity. Of note, we found that stage III CRC patients with high p38α levels display…

Abstract 1847: Anti-GARP antibody DS-1055a augments antitumor immunity by depleting highly suppressive GARP+ regulatory T cells

2021

Abstract Immune checkpoint blockers (ICBs) have drastically changed the clinical care of cancer; however, the population of patients who can benefit is relatively small because of intrinsic or acquired resistance to immune therapy. To evade immune destruction, tumors exploit several distinct strategies including immunosuppressive cells such as regulatory T (Treg) cells. Treg cells, an essential component for maintaining self-tolerance, inhibit antitumor immunity, consequently hindering protective cancer immunosurveillance and hampering effective antitumor immune responses in tumor-bearing hosts. It is often reported that a high ratio of Treg cells to effector CD8+ T cells is associated with…

Abstract B157: OX40 expression in tumor-associated Tregs as a potential prognostic biomarker and immunotherapeutic target in ovarian cancer

2016

Abstract Background - Treatment of ovarian cancer remains very challenging, with 80-85% of the cases still dying after relapse to standard chemotherapy, and alternative treatments are urgently needed. Expansion of regulatory T cells (Tregs) is considered the major factor limiting spontaneous immune responses to ovarian cancer. Agonist antibodies against the co-stimulatory receptor OX40 have recently demonstrated to abrogate Treg functions and are under clinical evaluation. We thus studied whether OX40 constituted a valid target of ovarian cancer-associated Tregs. Methods -Treg immunophenotypic analyses were performed by flow cytometry in ascites and ovarian cancer specimens and studied in a…

A bug in the resistance to EGFR inhibitors: is there a role for Mycoplasma and cytidine deaminase in reducing the activity of osimertinib in lung can…

2021

Identification of non-canonical NLRP3 functions in Th17 cells - Therapeutic interest to promote antitumor immune response

2021

Since decades, cancers have become a major public health issue, occupying the first premature mortality cause in France. One of the hallmarks of cancer cells is their ability to escape the immune system surveillance, notably through setting up an immunosuppressive environment within the tumor. The NLRP3 protein is largely studied in the inflammasome context, which is assembled in order to promote inflammation through IL-1β secretion. However, this protein also functions as a transcription factor in CD4+ T cells. Indeed, in Th2 cells, NLRP3 cooperate together with IRF4, to form a complex that is able to activate the transcription of Il4, Il5 and Il13, which are necessary for the function of …

Apoptosis induced in HepG2 cells by the synthetic cannabinoid WIN: involvement of the transcription factor PPARgamma.

2008

It has recently been shown that cannabinoids induce growth inhibition and apoptosis in different tumour cell lines. In the current study, the effects of WIN 55,212-2 (WIN), a synthetic and potent cannabinoid receptor agonist, are investigated in hepatoma HepG2 cells and a possible signal transduction pathway is proposed. In these cells, WIN induces a clear apoptotic effect which was accompanied by up-regulation of the death-signalling factors Bax, Bcl-X(S), t-Bid and down-regulation of the survival factors survivin, phospho-AKT, Hsp72 and Bcl-2. Moreover, WIN-induced apoptosis is associated with JNK/p38 MAPK pathway activation and mitochondrial depolarisation demonstrated by a cytofluorimet…

Cytotoxicity of oleanolic and ursolic acid derivatives toward hepatocellular carcinoma and evaluation of NF-κB involvement.

2019

Oleanolic and ursolic acids are two ubiquitous isomeric triterpene phytochemicals known for their anticancer activity. A set of derivatives of the two compounds with a modified oxidation state and lipophylicity at C-3 and C-28 positions, were prepared and tested as anticancer agents versus the lines HepG2, Hep3B and HA22T/VGH of hepatocarcinoma, a strongly aggressive tumor that is not responsive toward the standard therapies. New derivatives containing a three carbons side chain on the C-3 position were synthetized in both stereoisomeric forms by the Barbier-Grignard procedure and three of them were found to be active toward all of the three targets. The implication of the transcriptional n…

Role of IP3 Receptors in Shaping the Carotid Chemoreceptor Response to Hypoxia but not to Hypercapnia in the Rat Carotid Body: An Evidence Review

2021

This article addresses the disparity in the transduction pathways for hypoxic and hypercapnic stimuli in carotid body glomus cells. We investigated and reviewed the experimental evidence showing that the response to hypoxia, but not to hypercapnia, is mediated by 1,4,5-inositol triphosphate receptors (IP3R/s) regulating the intracellular calcium content [Ca2+]c in glomus cells. The rationale was based on the past observations that inhibition of oxidative phosphorylation leads to the explicit inhibition of the hypoxic chemoreflex. [Ca2+]c changes were measured using cellular Ca2+-sensitive fluorescent probes, and carotid sinus nerve (CSN) sensory discharge was recorded with bipolar electrode…

Transcriptional and post-transcriptional regulation of iNOS expression in human chondrocytes

2009

Chondrocytes are important for the development and maintenance of articular cartilage. However, both in osteoarthritis (OA) and rheumatoid arthritis (RA) chondrocytes are involved in the process of cartilage degradation and synthesize important immunomodulatory mediators, including nitric oxide (NO) generated by the inducible NO synthase (iNOS). To uncover the role of iNOS in the pathomechanisms of OA and RA, we analyzed the regulation of iNOS expression using immortalized human chondrocytes as a reproducible model. In C-28/I2 chondrocytes, iNOS expression was associated with the expression of the chondrocyte phenotype. Peak induction by a cytokine cocktail occurred between 6 and 8h and dec…

Cigarette Smoke Extract Induces p38 MAPK-Initiated, Fas-Mediated Eryptosis

2022

Eryptosis is a physiological mechanism for the clearance of senescent or damaged erythrocytes by phagocytes. Excessive eryptosis is stimulated under several pathologies and associated with endothelial injury and thrombosis. Cigarette smoke (CS) is an established risk factor for vascular diseases and cigarette smokers have high-levels of eryptotic erythrocytes. This study, for the first time, investigates the mechanism by which CS damages red blood cells (RBCs). CS extract (CSE) from commercial cigarettes was prepared and standardized for nicotine content. Cytofluorimetric analysis demonstrated that treatment of human RBCs with CSE caused dose-dependent, phosphatidylserine externalization an…