Targeting the p90RSK/MDM2/p53 Pathway Is Effective in Blocking Tumors with Oncogenic Up-Regulation of the MAPK Pathway Such as Melanoma and Lung Cancer.

In most human tumors, the MAPK pathway is constitutively activated. Since p90RSK is downstream of MAPK, it is often hyperactive and capable of phosphorylating oncogenic substrates. We have previously shown that p90RSK phosphorylates MDM2 at S166, promoting p53 degradation in follicular thyroid carcinomas.

Dietary Protein and Physical Exercise for the Treatment of Sarcopenia.

Sarcopenia is a multifactorial age-related disorder that causes a decrease in muscle mass, strength, and function, leading to alteration of movement, risk of falls, and hospitalization. This article aims to review recent findings on the factors underlying sarcopenia and the strategies required to delay and counteract its symptoms. We focus on molecular factors linked to ageing, on the role of low-grade chronic and acute inflammatory conditions such as cancer, which contributes to the onset of sarcopenia, and on the clinical criteria for its diagnosis.

Inhibition of Interleukin-6 Dependent Metalloproteinases-9/2 Expression in Cancer Cells by Diet Polyphenols.

Among inflammatory cytokines, Interleukin-6 (IL-6) is one of the major activators of acute phase response and is also involved in immune response and cancer progression. IL-6 is involved in the up-regulation of enzymes and growth factors acting on the extracellular matrix (ECM) remodelling components in physio-pathological processes. IL-6 enhances the expression of metalloproteases (MMP-)2/9, enzymes that play a key role in ECM degradation and therefore contribute to the process of tumor metastasis.

Emerging Targeted Therapeutic Strategies to Overcome Imatinib Resistance of Gastrointestinal Stromal Tumors.

Gastrointestinal stromal tumors (GISTs) are the most common malignant mesenchymal neoplasms of the gastrointestinal tract. The gold standard for the diagnosis of GISTs is morphologic analysis with an immunohistochemical evaluation plus genomic profiling to assess the mutational status of lesions. The majority of GISTs are driven by gain-of-function mutations in the proto-oncogene c- encoding the tyrosine kinase receptor (TKR) known as KIT and in the platelet-derived growth factor-alpha receptor () genes.

p90RSK Regulates p53 Pathway by MDM2 Phosphorylation in Thyroid Tumors.

The expression level of the tumor suppressor p53 is controlled by the E3 ubiquitin ligase MDM2 with a regulatory feedback loop, which allows p53 to upregulate its inhibitor MDM2. In this manuscript we demonstrated that p90RSK binds and phosphorylates MDM2 on serine 166 both in vitro and in vivo by kinase assay, immunoblot, and co-immunoprecipitation assay; this phosphorylation increases the stability of MDM2 which in turn binds p53, ubiquitinating it and promoting its degradation by proteasome. A pharmacological inhibitor of p90RSK, BI-D1870, decreases MDM2 phosphorylation, and restores p53 function, which in turn transcriptionally increases the expression of cell cycle inhibitor p21 and of pro-apoptotic protein Bax and downregulates the anti-apoptotic protein Bcl-2, causing a block of cell proliferation, measured by a BrdU assay and growth curve, and promoting apoptosis, measured by a TUNEL assay.

The Role of Nutrients in Prevention, Treatment and Post-Coronavirus Disease-2019 (COVID-19).

SARS-CoV-2 virus, infecting human cells via its spike protein, causes Coronavirus disease 2019 (COVID-19). COVID-19 is characterized by shortness of breath, fever, and pneumonia and is sometimes fatal. Unfortunately, to date, there is still no definite therapy to treat COVID-19.

Therapeutic Strategies Targeting Urokinase and Its Receptor in Cancer.

Several studies have ascertained that uPA and uPAR do participate in tumor progression and metastasis and are involved in cell adhesion, migration, invasion and survival, as well as angiogenesis. Increased levels of uPA and uPAR in tumor tissues, stroma and biological fluids correlate with adverse clinic-pathologic features and poor patient outcomes. After binding to uPAR, uPA activates plasminogen to plasmin, a broad-spectrum matrix- and fibrin-degrading enzyme able to facilitate tumor cell invasion and dissemination to distant sites.

ω-3 and ω-6 Polyunsaturated Fatty Acids, Obesity and Cancer.

Recently, nutraceutical bioactive compounds in foods have been discovered for their potential health benefits regarding the prevention of chronic disorders, such as cancer, and inflammatory, cardiovascular, and metabolic diseases. Dietary omega-3 polyunsaturated fatty acids (ω-3PUFAs), including alpha-linolenic acid, docosapentaenoic acid, and eicosapentaenoic acid, are mostly attractive. They are available for the customers worldwide from commonly used foods and/or as components of commercial food supplements.

MicroRNAs as Key Players in Melanoma Cell Resistance to MAPK and Immune Checkpoint Inhibitors.

Advances in the use of targeted and immune therapies have revolutionized the clinical management of melanoma patients, prolonging significantly their overall and progression-free survival. However, both targeted and immune therapies suffer limitations due to genetic mutations and epigenetic modifications, which determine a great heterogeneity and phenotypic plasticity of melanoma cells. Acquired resistance of melanoma patients to inhibitors of BRAF (BRAFi) and MEK (MEKi), which block the mitogen-activated protein kinase (MAPK) pathway, limits their prolonged use.

Targeting the Formyl Peptide Receptor type 1 to prevent the adhesion of ovarian cancer cells onto mesothelium and subsequent invasion.

Background: The biological behavior of epithelial ovarian cancer (EOC) is unique since EOC cells metastasize early to the peritoneum. Thereby, new anti-target agents designed to block trans-coelomic dissemination of EOC cells may be useful as anti-metastatic drugs. The Urokinase Plasminogen Activator Receptor (uPAR) is overexpressed in EOC tissues, and its truncated forms released in sera and/or ascitic fluid are associated with poor prognosis and unfavorable clinical outcome.

Minireview: The Epigenetic Modulation of in Reproduction and Cancer.

Epigenetics describes how both lifestyle and environment may affect human health through the modulation of genome functions and without any change to the DNA nucleotide sequence. The discovery of several epigenetic mechanisms and the possibility to deliver epigenetic marks in cells, gametes, and biological fluids has opened up new perspectives in the prevention, diagnosis, and treatment of human diseases. In this respect, the depth of knowledge of epigenetic mechanisms is fundamental to preserving health status and to developing targeted interventions.

Role of Microenvironment on the Fate of Disseminating Cancer Stem Cells.

Disseminating Cancer Stem Cells (CSCs) initiate growth in specific niches of the host tissues, the cellular and molecular components of which sustain signaling pathways that support their survival, self-renewal dormancy and reactivation. In the metastatic niche, tumor cells may enter in a dormant state to survive and, consequently, the metastasis can remain latent for years. Despite the clinical importance of metastatic latency, little is known about what induces CSCs to enter a dormant state and what allows them to remain viable for years in this state.

Effect of ABT-888 on the apoptosis, motility and invasiveness of BRAFi-resistant melanoma cells.

Melanoma is a molecularly heterogeneous disease with many genetic mutations and altered signaling pathways. Activating mutations in the BRAF oncogene are observed in approximately 50% of cutaneous melanomas and the use of BRAF inhibitor (BRAFi) compounds has been reported to improve the outcome of patients with BRAF-mutated metastatic melanoma. However, the majority of these patients develop resistance within 6-8 months following the initiation of BRAFi treatment.

Controversial Role of Kisspeptins/KiSS-1R Signaling System in Tumor Development.

was first described as a metastasis suppressor gene in malignant melanoma. encodes a 145 amino-acid residue peptide that is further processed, producing the 54 amino acid metastin and shorter peptides collectively named kisspeptins (KPs). KPs bind and activate KiSS-1R (GPR54).

Targeting the cross-talk between Urokinase receptor and Formyl peptide receptor type 1 to prevent invasion and trans-endothelial migration of melanoma cells.

Background: Accumulating evidence demonstrates that the Urokinase Receptor (uPAR) regulates tumor cell migration through its assembly in composite regulatory units with transmembrane receptors, and uPAR is the minimal sequence required to induce cell motility through the Formyl Peptide Receptor type 1 (FPR1). Both uPAR and FPR1 are involved in melanoma tumor progression, suggesting that they may be targeted for therapeutic purposes. In this study, the role of the uPAR-FPR1 cross-talk to sustain melanoma cell ability to invade extracellular matrix and cross endothelial barriers is investigated.

MicroRNAs, Cancer and Diet: Facts and New Exciting Perspectives.

Background: MicroRNAs (miRNAs) are small non-coding RNAs able to regulate gene expression at multiple levels. They are detected in tissues, blood, and other body fluids with high stability and have a recognized role in maintaining of tissue homeostasis. Aberrant expression profile of miRNAs has been observed in several diseases, primarily cancer.

Retro-inverso Urokinase Receptor Antagonists for the Treatment of Metastatic Sarcomas.

The development of metastases is a multistep process that requires the activation of physiological and biochemical processes that govern migration, invasion and entry of metastatic cells into blood vessels. The urokinase receptor (uPAR) promotes cell migration by interacting with the Formyl Peptide Receptors (FPRs). Since both uPAR and FPR1 are involved in tumor progression, the uPAR-FPR1 interaction is an attractive therapeutic target.

Melanoma and immunotherapy bridge 2015 : Naples, Italy. 1-5 December 2015.

MELANOMA BRIDGE 2015 KEYNOTE SPEAKER PRESENTATIONS Molecular and immuno-advances K1 Immunologic and metabolic consequences of PI3K/AKT/mTOR activation in melanoma Vashisht G. Y. Nanda, Weiyi Peng, Patrick Hwu, Michael A.

The urokinase receptor-derived cyclic peptide [SRSRY] suppresses neovascularization and intravasation of osteosarcoma and chondrosarcoma cells.

The receptor for the urokinase-type plasminogen activator (uPAR) is a widely recognized master regulator of cell migration and uPAR88-92 is the minimal sequence required to induce cell motility and angiogenesis by interacting with the formyl peptide receptor type 1 (FPR1). In this study, we present evidence that the cyclization of the uPAR88-92 sequence generates a new potent inhibitor of migration, and extracellular matrix invasion of human osteosarcoma and chondrosarcoma cells expressing comparable levels of FPR1 on cell surface. In vitro, the cyclized peptide [SRSRY] prevents formation of capillary-like tubes by endothelial cells co-cultured with chondrosarcoma cells and trans-endothelial migration of osteosarcoma and chondrosarcoma cells.

Cyclization of the urokinase receptor-derived ser-arg-ser-arg-tyr Peptide generates a potent inhibitor of trans-endothelial migration of monocytes.

The receptor for the urokinase-type plasminogen activator (uPAR) is a widely recognized master regulator of cell migration and uPAR88-92 is the minimal sequence required to induce cell motility. We and others have previously documented that the uPAR88-92 sequence, even in the form of synthetic linear peptide (SRSRY), interacts with the formyl peptide receptor type 1 (FPR1), henceforth inducing cell migration of several cell lines, including monocytes. FPR1 is mainly expressed by mammalian phagocytic leukocytes and plays a crucial role in chemotaxis.

AurkA inhibitors enhance the effects of B-RAF and MEK inhibitors in melanoma treatment.

Background: Aurora kinase A (AurkA) is over-expressed in melanoma and its inhibition has been observed to limit tumor growth, suggesting a potential role in melanoma treatment.

Methods: A human melanoma cell line with the B-RAF (V600E) mutation (A375mel) was exposed to B-RAF inhibitor (GSK2118436), MEK inhibitor (GSK1120212) and AurkA inhibitor (MLN8054) as single agents or in various combinations (BRAF plus AurkA inhibitor, MEK plus AurkA inhibitor or triple combination BRAF plus MEK plus AurkA inhibitor). Cell proliferation was assessed using xCELLigence technology.

Loss of p27 expression through RAS-->BRAF-->MAP kinase-dependent pathway in human thyroid carcinomas.

In the present study, we report that the RAS/BRAF/MAP kinase cascade plays a crucial role in the regulation of the Skp2/p27 pathway in thyroid cancer cells and that this is critical for cell proliferation. In vitro studies with cellular models of human thyroid carcinoma cells demonstrated that the adoptive expression of oncogenic RET/PTC1, Ha-RASV12 or BRAFV600E enhances Skp2 and reduces p27 protein expression in a MAP kinase-dependent manner; that RAS/BRAF/MAP kinase-dependent control of p27 expression in thyroid cancer cells occurs by regulating the stability of Skp2 and p27 protein; and that antisense oligonucleotides to p27 suppress growth arrest induced by MEK inhibitors. Finally, analysis of human thyroid carcinomas indicated that MAP kinase-positive thyroid tumors-as detected by immunostaining for p-ERK - presented high p27 degradative activity and low levels of p27 protein (n = 30; p < 0.

Overexpression of the S-phase kinase-associated protein 2 in thyroid cancer.

Loss of expression of the cyclin-dependent kinase inhibitor p27 through enhanced protein degradation frequently occurs in human cancer. Degradation of p27 requires ubiquitination by the S-phase kinase-associated protein 2 (Skp2), a member of the F-box family of Skp1-Cullin-F-box protein ubiquitin ligases. In the present study, we have investigated the role of Skp2 in human thyroid tumours.

The transcriptional repressor DREAM is involved in thyroid gene expression.

Downstream regulatory element antagonistic modulator (DREAM) was originally identified in neuroendocrine cells as a calcium-binding protein that specifically binds to downstream regulatory elements (DRE) on DNA, and represses transcription of its target genes. To explore the possibility that DREAM may regulate the endocrine activity of the thyroid gland, we analyzed its mRNA expression in undifferentiated and differentiated thyroid cells. We demonstrated that DREAM is expressed in the normal thyroid tissue as well as in differentiated thyroid cells in culture while it is absent in FRT poorly differentiated cells.

Complex regulation of the cyclin-dependent kinase inhibitor p27kip1 in thyroid cancer cells by the PI3K/AKT pathway: regulation of p27kip1 expression and localization.

Functional inactivation of the tumor suppressor p27(kip1) in human cancer occurs either through loss of expression or through phosphorylation-dependent cytoplasmic sequestration. Here we demonstrate that dysregulation of the PI3K/AKT pathway is important in thyroid carcinogenesis and that p27(kip1) is a key target of the growth-regulatory activity exerted by this pathway in thyroid cancer cells. Using specific PI3K inhibitors (LY294002, wortmannin, and PTEN) and a dominant active AKT construct (myrAKT), we demonstrated that the PI3K/AKT pathway controlled thyroid cell proliferation by regulating the expression and subcellular localization of p27.