Ganglioside GD2 Contributes to a Stem-Like Phenotype in Intrahepatic Cholangiocarcinoma.

Background & Aims: GD2, a member of the ganglioside (GS) family (sialic acid-containing glycosphingolipids), is a potential biomarker of cancer stem cells (CSC) in several tumours. However, the possible role of GD2 and its biosynthetic enzyme, GD3 synthase (GD3S), in intrahepatic cholangiocarcinoma (iCCA) has not been explored.

Methods: The stem-like subset of two iCCA cell lines was enriched by sphere culture (SPH) and compared to monolayer parental cells (MON).

ERK5 mediates pro-tumorigenic phenotype in non-small lung cancer cells induced by PGE2.

Lung cancer is the leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) constituting approximately 84 % of all lung cancer cases. The role of inflammation in the initiation and progression of NSCLC tumors has been the focus of extensive research. Among the various inflammatory mediators, prostaglandin E2 (PGE2) plays a pivotal role in promoting the aggressiveness of epithelial tumors through multiple mechanisms, including the stimulation of growth, evasion of apoptosis, invasion, and induction of angiogenesis.

Importin subunit beta-1 mediates ERK5 nuclear translocation, and its inhibition synergizes with ERK5 kinase inhibitors in reducing cancer cell proliferation.

The mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase 5 (ERK5) is emerging as a promising target in cancer. Indeed, alterations of the MEK5/ERK5 pathway are present in many types of cancer, including melanoma. One of the key events in MAPK signalling is MAPK nuclear translocation and its subsequent regulation of gene expression.

Latent-Transforming Growth Factor β-Binding Protein 1/Transforming Growth Factor β1 Complex Drives Antitumoral Effects upon ERK5 Targeting in Melanoma.

Melanoma is the deadliest skin cancer, with a poor prognosis in advanced stages. While available treatments have improved survival, long-term benefits are still unsatisfactory. The mitogen-activated protein kinase extracellular signal-regulated kinase 5 (ERK5) promotes melanoma growth, and ERK5 inhibition determines cellular senescence and the senescence-associated secretory phenotype.

Sphingosine 1-phosphate elicits a ROS-mediated proinflammatory response in human endometrial stromal cells via ERK5 activation.

Endometriosis is a chronic gynecological disease affecting ~10% women in the reproductive age characterized by the growth of endometrial glands and stroma outside the uterine cavity. The inflammatory process has a key role in the initiation and progression of the disorder. Currently, there are no available early diagnostic tests and therapy relies exclusively on symptomatic drugs, so that elucidation of the complex molecular mechanisms involved in the pathogenesis of endometriosis is an unmet need.

Pathophysiological Impact of the MEK5/ERK5 Pathway in Oxidative Stress.

Oxidative stress regulates many physiological and pathological processes. Indeed, a low increase in the basal level of reactive oxygen species (ROS) is essential for various cellular functions, including signal transduction, gene expression, cell survival or death, as well as antioxidant capacity. However, if the amount of generated ROS overcomes the antioxidant capacity, excessive ROS results in cellular dysfunctions as a consequence of damage to cellular components, including DNA, lipids and proteins, and may eventually lead to cell death or carcinogenesis.

MAPK15 protects from oxidative stress-dependent cellular senescence by inducing the mitophagic process.

Mitochondria are the major source of reactive oxygen species (ROS), whose aberrant production by dysfunctional mitochondria leads to oxidative stress, thus contributing to aging as well as neurodegenerative disorders and cancer. Cells efficiently eliminate damaged mitochondria through a selective type of autophagy, named mitophagy. Here, we demonstrate the involvement of the atypical MAP kinase family member MAPK15 in cellular senescence, by preserving mitochondrial quality, thanks to its ability to control mitophagy and, therefore, prevent oxidative stress.

Targeting MAPK in Cancer 2.0.

Mitogen-activated protein kinase (MAPK) pathways are prominently involved in the onset and progression of cancer [...

Macrophage MerTK promotes profibrogenic cross-talk with hepatic stellate cells via soluble mediators.

Background & Aims: Activation of Kupffer cells and recruitment of monocytes are key events in fibrogenesis. These cells release soluble mediators which induce the activation of hepatic stellate cells (HSCs), the main fibrogenic cell type within the liver. Mer tyrosine kinase (MerTK) signaling regulates multiple processes in macrophages and has been implicated in the pathogenesis of non-alcoholic steatohepatitis-related fibrosis.

Lactate Maintains BCR/Abl Expression and Signaling in Chronic Myeloid Leukemia Cells Under Nutrient Restriction.

This study was directed to deepen the effects of nutrient shortage on BCR/Abl expression and signaling in chronic myeloid leukemia (CML) cells. The backbone of the study was cell culture in medium lacking glucose, the consumption of which we had previously shown to drive BCR/Abl suppression, and glutamine, the other main nutrient besides glucose. In this context, we focused on the role of lactate, the main by-product of glucose metabolism under conditions of rapid cell growth, in particular as a modulator of the maintenance of CML stem/progenitor cell potential, a crucial determinant of disease course and relapse of disease.

Inhibition of ERK5 Elicits Cellular Senescence in Melanoma via the Cyclin-Dependent Kinase Inhibitor p21.

Melanoma is the deadliest skin cancer with a very poor prognosis in advanced stages. Although targeted and immune therapies have improved survival, not all patients benefit from these treatments. The mitogen-activated protein kinase ERK5 supports the growth of melanoma cells and .

The Hedgehog-GLI Pathway Regulates MEK5-ERK5 Expression and Activation in Melanoma Cells.

Malignant melanoma is the deadliest skin cancer, with a poor prognosis in advanced stages. We recently showed that the extracellular signal-regulated kinase 5 (ERK5), encoded by the gene, plays a pivotal role in melanoma by regulating cell functions necessary for tumour development, such as proliferation. Hedgehog-GLI signalling is constitutively active in melanoma and is required for proliferation.

Hepatocyte-Specific Deletion of HIF2α Prevents NASH-Related Liver Carcinogenesis by Decreasing Cancer Cell Proliferation.

Background & Aims: Hypoxia and hypoxia-inducible factors (HIFs) are involved in chronic liver disease progression. We previously showed that hepatocyte HIF-2α activation contributed significantly to nonalcoholic fatty liver disease progression in experimental animals and human patients. In this study, using an appropriate genetic murine model, we mechanistically investigated the involvement of hepatocyte HIF-2α in experimental nonalcoholic steatohepatitis (NASH)-related carcinogenesis.

Glutamine Availability Controls BCR/Abl Protein Expression and Functional Phenotype of Chronic Myeloid Leukemia Cells Endowed with Stem/Progenitor Cell Potential.

This study was directed to characterize the role of glutamine in the modulation of the response of chronic myeloid leukemia (CML) cells to low oxygen, a main condition of hematopoietic stem cell niches of bone marrow. Cells were incubated in atmosphere at 0.2% oxygen in the absence or the presence of glutamine.

Extracellular Signal-Regulated Kinase 5 Regulates the Malignant Phenotype of Cholangiocarcinoma Cells.

Background And Aims: Cholangiocarcinoma (CCA) is characterized by high resistance to chemotherapy and poor prognosis. Several oncogenic pathways converge on activation of extracellular signal-regulated kinase 5 (ERK5), whose role in CCA has not been explored. The aim of this study was to investigate the role of ERK5 in the biology of CCA.

Playing the Whack-A-Mole Game: ERK5 Activation Emerges Among the Resistance Mechanisms to RAF-MEK1/2-ERK1/2- Targeted Therapy.

Molecularly tailored therapies have opened a new era, chronic myeloid leukemia being the ideal example, in the treatment of cancer. However, available therapeutic options are still unsatisfactory in many types of cancer, and often fail due to the occurrence of resistance mechanisms. With regard to small-molecule compounds targeting the components of the Mitogen-Activated Protein Kinase (MAPK) cascade RAF-MEK1/2-ERK1/2, these drugs may result ineffective as a consequence of the activation of compensatory pro-survival/proliferative signals, including receptor tyrosine kinases, PI3K, as well as other components of the MAPK family such as TPL2/COT.

Enhanced Antitumoral Activity and Photoacoustic Imaging Properties of AuNP-Enriched Endothelial Colony Forming Cells on Melanoma.

Near infrared (NIR)-resonant gold nanoparticles (AuNPs) hold great promise in cancer diagnostics and treatment. However, translating the theranostic potential of AuNPs into clinical applications still remains a challenge due to the difficulty to improve the efficiency and specificity of tumor delivery in vivo as well as the clearance from liver and spleen to avoid off target toxicity. In this study, endothelial colony forming cells (ECFCs) are exploited as vehicles to deliver AuNPs to tumors.

Pathogenic mechanism and modeling of neuroferritinopathy.

Neuroferritinopathy is a rare autosomal dominant inherited movement disorder caused by alteration of the L-ferritin gene that results in the production of a ferritin molecule that is unable to properly manage iron, leading to the presence of free redox-active iron in the cytosol. This form of iron has detrimental effects on cells, particularly severe for neuronal cells, which are highly sensitive to oxidative stress. Although very rare, the disorder is notable for two reasons.

In Vitro Comparison of the Effects of Imatinib and Ponatinib on Chronic Myeloid Leukemia Progenitor/Stem Cell Features.

Background: The development of molecularly tailored therapeutic agents such as the BCR/ABL-active tyrosine kinase inhibitors (TKi) resulted in an excellent treatment option for chronic myeloid leukemia (CML) patients. However, following TKi discontinuation, disease relapses in 40-60% of patients, an occurrence very likely due to the persistence of leukemic stem cells that are scarcely sensitive to TKi. Nevertheless, TKi are still the only current treatment option for CML patients.

Beyond Kinase Activity: ERK5 Nucleo-Cytoplasmic Shuttling as a Novel Target for Anticancer Therapy.

The importance of mitogen-activated protein kinases (MAPK) in human pathology is underlined by the relevance of abnormalities of MAPK-related signaling pathways to a number of different diseases, including inflammatory disorders and cancer. One of the key events in MAPK signaling, especially with respect to pro-proliferative effects that are crucial for the onset and progression of cancer, is MAPK nuclear translocation and its role in the regulation of gene expression. The extracellular signal-regulated kinase 5 (ERK5) is the most recently discovered classical MAPK and it is emerging as a possible target for cancer treatment.

The protein kinase CK2 contributes to the malignant phenotype of cholangiocarcinoma cells.

Cholangiocarcinoma (CCA) is a particularly aggressive hepatobiliary malignancy, for which the molecular mechanisms underlying the malignant phenotype are still poorly understood, and novel and effective therapeutic strategies are limited. The pro-survival protein kinase CK2 is frequently overexpressed in cancer and is receiving increasing interest as an anti-tumor drug target. Its precise role in CCA biology is still largely unknown.

Antitumor Activity of a Novel Fibroblast Growth Factor Receptor Inhibitor for Intrahepatic Cholangiocarcinoma.

Fibroblast growth factor receptor 2 (FGFR2) might have an important role in the pathogenesis and biology of cholangiocarcinoma (CCA). We examined FGFR expression in CCA tumor specimens obtained from patients and CCA cell lines, and then determined the effects of the novel FGFR inhibitor, derazantinib (DZB; formally, ARQ 087), which is currently in clinical phase 2 trials for intrahepatic CCA. DZB inhibited the growth of CCA cell lines in a dose-dependent manner, and extracellular signal-regulated kinase 1/2 and AKT.