ABSTRACT
The Na+ ionophore monensin affects cellular pH and, depending on its concentration, causes the survival or death of tumor cells. In the present study, we elucidated the survival pathway activated in U937 cells, a human lymphoma-derived cell line. These cells treated with monensin at a concentration of 5 µM were growth-arrested in G1, activated p38 mitogen-activated protein kinase (MAPK) and showed an increased expression of cyclooxygenase-2 (COX-2). The latter two molecular events were linked, as pharmacological inhibition of the MAPK did not allow COX-2 increased expression. Furthermore, we showed that p38 and COX-2 keep monensin-stressed U937 cells alive, as pharmacological inhibition of each enzyme caused cell death.
Subject(s)
Cell Survival/genetics , Cyclooxygenase 2/biosynthesis , p38 Mitogen-Activated Protein Kinases/metabolism , Cell Cycle Checkpoints/drug effects , Cell Cycle Checkpoints/genetics , Cell Death/drug effects , Cell Death/genetics , Cell Line, Tumor , Cell Survival/drug effects , Cyclooxygenase 2/genetics , Cyclooxygenase 2/metabolism , Enzyme Induction , G1 Phase/drug effects , G1 Phase/genetics , Humans , Monensin/pharmacology , Signal Transduction , U937 Cells , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/geneticsABSTRACT
BACKGROUND: Epidemiological studies revealed significantly lower mortality rates in cancer patients receiving cardiac glycosides, which turned on interest in the anticancer properties of these drugs. However, cardiac glycosides have also been shown to stimulate cell growth in several cell types. In the present investigation we analyzed the pro-death and pro-survival properties of ouabain in the human lymphoma derived cell line U937. METHODS: ROS, intracellular Ca++, cell cycle were evaluated by loading the cells with fluorescent probes under cytofluorimetry. Cell counts and evaluation of trypan blue-excluding cells were performed under optic microscope. Protein detection was done by specific antibodies after protein separation from cellular lysates by SDS-PAGE and transfer blot. RESULTS: High doses of ouabain cause ROS generation, elevation of [Ca++]i and death of lymphoma derived U937 cells. Lower doses of OUA activate a survival pathway in which plays a role the Na+/Ca++-exchanger (NCX), active in the Ca++ influx mode rather than in the Ca++ efflux mode. Also p38 MAPK plays a pro-survival role. However, the activation of this MAPK does not appear to depend on NCX. CONCLUSION: This investigation shows that the cardiac glycoside OUA is cytotoxic also for the lymphoma derived cell line U937 and that can activate a survival pathway in which are involved NCX and p38 MAPK. These molecules can represent potential targets of combined therapy.
Subject(s)
Calcium/metabolism , Ouabain/administration & dosage , Reactive Oxygen Species/metabolism , Sodium-Calcium Exchanger , Cell Death/drug effects , Cell Survival/drug effects , Flow Cytometry , Gene Expression Regulation, Neoplastic/drug effects , Humans , Lymphoma/genetics , Lymphoma/metabolism , Sodium-Calcium Exchanger/drug effects , Sodium-Calcium Exchanger/metabolism , U937 Cells , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
In the present study we assessed the contribution of the two hemispheres to the attribution of gender of faces in male and female observers. Normal and chimeric faces were presented in their canonical orientation and upside-down in a tachistoscopic paradigm. Chimeric faces were composed of two halves (left and right) obtained from photos of individuals of the same sex or from individuals of different sexes. All faces were presented tachistoscopically with a central fixation, the two halves falling in the two visual fields of the observer, who was required to rapidly judge the sex of the face. A left half-face (right-hemispheric) bias for gender attribution with upright faces was observed both in male and female participants, as previously reported. Strikingly, however, the bias depended entirely on female-left/male-right chimeras, revealing a right-hemispheric advantage for the recognition of female faces. The results are discussed in the light of a behavioural bias during development (i.e., maternal cradling).
