Sulconazole inhibits PD-1 expression in immune cells and cancer cells malignant phenotype through NF-κB and calcium activity repression.

The overexpression of the immunoinhibitory receptor programmed death-1 (PD1) on T-cells is involved in immune evasion in cancer. The use of anti-PD-1/PDL-1 strategy has deeply changed the therapies of cancers and patient survival. However, their efficacy diverges greatly along with tumor type and patient populations.

[Mechanisms of cancer drug resistance].

Despite decades of research into the molecular mechanisms of cancer and the development of new treatments, drug resistance persists as a major problem. This is in part due to the heterogeneity of cancer, including the diversity of tumor cell lineage and cell plasticity, the spectrum of somatic mutations, the complexity of microenvironments, and immunosuppressive characteristic, then necessitating the use of many different therapeutic approaches. We summarize here the biological causes of resistance, thus offering new perspectives for tackle drug resistance.

Integrative analysis of genomic and transcriptomic alterations of and in cancer.

The and genes have been shown by numerous groups to be functionally associated with adenocarcinoma progression and metastasis. In this paper, we explore the data available in databases concerning genomic and transcriptomic features of these two genes: the NCBI dbSNP database was used to explore the presence and roles of constitutional SNPs, and the NCI, Cancer Cell Line Encyclopedia (CCLE) and TCGA databases were used to explore somatic mutations and copy number variations (CNVs), as well as mRNA expression of these genes in human cancer cell lines and tumours. Relationships of / expression with whole-genome mRNA expression and cancer features (i.

[Normal organoids and their applications in cancer research].

Three-dimensional (3D) culture of organoids from primary cells (wild type) or tumoroids from tumor cells, is used to study the physiological mechanisms in vivo, in order to model normal or tumor tissues more accurately than conventional two-dimensional (2D) culture. The features of this 3D culture, such as the three-dimensional structure, the self-renewal capacity and differentiation are preserved and appropriate to cancer study since their cellular characteristics are very similar to in vivo models. Here, we summarize the recent advances in the rapidly evolving field of organoids and their applications to cancer biology, clinical research and personalized medicine.

The Anterior GRadient (AGR) family proteins in epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is the most common gynecologic disorder. Even with the recent progresses made towards the use of new therapeutics, it still represents the most lethal gynecologic malignancy in women from developed countries.The discovery of the anterior gradient proteins AGR2 and AGR3, which are highly related members belonging to the protein disulfide isomerase (PDI) family, attracted researchers' attention due to their putative involvement in adenocarcinoma development.

Extracellular AGR2 triggers lung tumour cell proliferation through repression of p21.

The human Anterior GRadient 2 (AGR2) protein is an Endoplasmic Reticulum (ER)-resident protein which belongs to the Protein-Disulfide Isomerase (PDI) superfamily and is involved to productive protein folding in the ER. As such AGR2, often found overexpressed in adenocarcinomas, contributes to tumour development by enhancing ER proteostasis. We previously demonstrated that AGR2 is secreted (extracellular AGR2 (eAGR2)) in the tumour microenvironment and plays extracellular roles independent of its ER functions.

Patients Lung Derived Tumoroids (PLDTs) to model therapeutic response.

Preclinical lung cancer models are essential for a basic understanding of lung cancer biology and its translation into efficient treatment options for affected patients. Lung cancer cell lines and xenografts derived directly from human lung tumors have proven highly valuable in fundamental oncology research and anticancer drug discovery. Both models inherently comprise advantages and caveats that have to be accounted for.

Cytochrome P450 1B1 polymorphism drives cancer cell stemness and patient outcome in head-and-neck carcinoma.

Background: Cytochrome P450 1B1 (CYP1B1) is mostly expressed in tumours and displays unusual properties. Its two polymorphic forms were differently associated with anticancer drug sensitivity. We decipher here the role of this polymorphism in anticancer drug efficacy in vitro, in vivo and in the clinical setting.

The anterior gradient-2 interactome.

The anterior gradient-2 (AGR2) is an endoplasmic reticulum (ER)-resident protein belonging to the protein disulfide isomerase family that mediates the formation of disulfide bonds and assists the protein quality control in the ER. In addition to its role in proteostasis, extracellular AGR2 is responsible for various cellular effects in many types of cancer, including cell proliferation, survival, and metastasis. Various OMICs approaches have been used to identify AGR2 binding partners and to investigate the functions of AGR2 in the ER and outside the cell.

Extracellular AGR3 regulates breast cancer cells migration via Src signaling.

Human anterior gradient proteins AGR2 and AGR3 are overexpressed in a variety of adenocarcinomas and are often secreted in cancer patients' specimens, which suggests a role for AGR proteins in intra and extracellular compartments. Although these proteins exhibit high sequence homology, AGR2 is predominantly described as a pro-oncogene and a potential prognostic biomarker. However, little is known about the function of AGR3.

Inactivation of Proprotein Convertases in T Cells Inhibits PD-1 Expression and Creates a Favorable Immune Microenvironment in Colorectal Cancer.

Proprotein convertases (PC) activate precursor proteins that play crucial roles in various cancers. In this study, we investigated whether PC enzyme activity is required for expression of the checkpoint protein programmed cell death protein 1 (PD-1) on cytotoxic T lymphocytes (CTL) in colon cancer. Although altered expression of the PC secretory pathway was observed in human colon cancers, only furin showed highly diffuse expression throughout the tumors.

The role of protein disulphide isomerase AGR2 in the tumour niche.

In recent years, the discovery of 'tumour niche', a microenvironment that favours tumour development has changed our perspective of cancer. This microenvironment generated by the tumour cells itself and surrounding cells is capable of providing essential elements for its growth. Consequently, the homoeostasis of the secretory pathway (SP) has become an essential player in cancer development.

Secretion of protein disulphide isomerase AGR2 confers tumorigenic properties.

The extracellular matrix (ECM) plays an instrumental role in determining the spatial orientation of epithelial polarity and the formation of lumens in glandular tissues during morphogenesis. Here, we show that the Endoplasmic Reticulum (ER)-resident protein anterior gradient-2 (AGR2), a soluble protein-disulfide isomerase involved in ER protein folding and quality control, is secreted and interacts with the ECM. Extracellular AGR2 (eAGR2) is a microenvironmental regulator of epithelial tissue architecture, which plays a role in the preneoplastic phenotype and contributes to epithelial tumorigenicity.

Proteomic remodeling of proteasome in right heart failure.

The development of right heart failure (RHF) is characterized by alterations of right ventricle (RV) structure and function, but the mechanisms of RHF remain still unknown. Thus, understanding the RHF is essential for improved therapies. Therefore, identification by quantitative proteomics of targets specific to RHF may have therapeutic benefits to identify novel potential therapeutic targets.

P97/CDC-48: proteostasis control in tumor cell biology.

P97/CDC-48 is a prominent member of a highly evolutionary conserved Walker cassette - containing AAA+ATPases. It has been involved in numerous cellular processes ranging from the control of protein homeostasis to membrane trafficking through the intervention of specific accessory proteins. Expression of p97/CDC-48 in cancers has been correlated with tumor aggressiveness and prognosis, however the precise underlying molecular mechanisms remain to be characterized.

Three-dimensional culture model to distinguish normal from malignant human bronchial epithelial cells.

In the present study, we have developed an in vitro three-dimensional model to differentiate normal lung cells from lung cancer cells in order to study the mechanisms resulting in lung cancer. Using a reconstituted laminin-rich basement membrane (Matrigel), we were able to culture normal human bronchial epithelial cells and a subset of malignant cells. The two cell types can be readily distinguished by the ability of normal cells to express a structurally and functionally differentiated phenotype within Matrigel.

Role of Phosphorylation in the Control of Clathrin-Mediated Internalization of GPCR.

The process by which G protein-coupled receptors (GPCRs) are internalized through the clathrin-coated vesicles involves interactions of multifunctional adaptor proteins. These interactions are tightly controlled by phosphorylation and dephosphorylation mechanisms resulting in the regulation of receptor endocytosis. However, the identities of the kinases involved in this process remained largely unknown until recently.

Primary cilium-dependent and -independent Hedgehog signaling inhibits p16(INK4A).

In a genome-wide siRNA analysis of p16(INK4a) (p16) modulators, we identify the Hedgehog (Hh) pathway component SUFU and formally demonstrate that Hh signaling promotes mitogenesis by suppression of p16. A fragment of the Hh-responsive GLI2 transcription factor directly binds and inhibits the p16 promoter and senescence is associated with the loss of nuclear GLI2. Hh components partially reside in the primary cilium (PC), and the small fraction of cells in mass culture that elaborate a PC have the lowest expression of p16.

ARF6 regulates angiotensin II type 1 receptor endocytosis by controlling the recruitment of AP-2 and clathrin.

We have previously shown that the ADP-ribosylation factor 6 (ARF6), a small GTP-binding protein, is important for the internalization of several G protein-coupled receptors. Here, we propose to elucidate the molecular steps controlled by ARF6 in the endocytic process of the angiotensin II type 1 receptor (ATR), a model receptor being internalized via the clathrin-coated vesicle pathway. In HEK 293 cells, angiotensin II stimulation leads to the formation of a complex including ARF6, the beta-subunit of AP-2 and the heavy chain of clathrin.

Unraveling G protein-coupled receptor endocytosis pathways using real-time monitoring of agonist-promoted interaction between beta-arrestins and AP-2.

The most widely studied pathway underlying agonist-promoted internalization of G protein-coupled receptors (GPCRs) involves beta-arrestin and clathrin-coated pits. However, both beta-arrestin- and clathrin-independent processes have also been reported. Classically, the endocytic routes are characterized using pharmacological inhibitors and various dominant negative mutants, resulting sometimes in conflicting results and interpretational difficulties.

Src-dependent phosphorylation of beta2-adaptin dissociates the beta-arrestin-AP-2 complex.

Beta-arrestins are known to act as endocytic adaptors by recruiting the clathrin adaptor protein 2 (AP-2) complex to G-protein-coupled receptors (GPCRs), linking them to clathrin-coated pits (CCPs) for internalization. They also act as signaling molecules connecting GPCRs to different downstream effectors. We have previously shown that stimulation of the angiotensin II (Ang II) type 1 receptor (AGTR1, hereafter referred to as AT1R), a member of the GPCR family, promotes the formation of a complex between beta-arrestin, the kinase Src and AP-2.