ABSTRACT
Cancer is a multifactorial disease that constitutes a serious public health problem worldwide. Prostate cancer advanced stages are associated with the development of androgen-independent tumors and an apoptosis-resistant phenotype that progresses to metastasis. By studying androgen-independent lymphoid nodule carcinoma of the prostate (LNCaP) cells induced to apoptosis by serum elimination, we identified the activation of a non-selective cationic channel of 23pS conductance that promotes incoming Ca2+ currents, as well as apoptosis final stages. arp2cDNA was isolated and identified to be of the same cell type, and mRNA was expressed in Xenopus laevis oocytes, which was found to be associated with the activation of incoming Ca2+ currents and induction to apoptosis. cDNA, which encodes the ARP2 protein, was overexpressed in LNCaP cells and Chinese hamster ovary cells, which induced apoptosis. Our evidence suggests that protein ARP2 overexpression and transit to the cell membrane allows an increased Ca2+ incoming current that initiates the apoptosis process in epithelial-type cells whose phenotype shows resistance to programmed cell death.
Subject(s)
Humans , Animals , Male , Prostatic Neoplasms/pathology , Calcium/metabolism , Apoptosis/physiology , Apoptosis Regulatory Proteins/metabolism , Ovum/metabolism , Prostatic Neoplasms/metabolism , Xenopus laevis , RNA, Messenger/metabolism , Calcium Channels/metabolism , Cricetulus , CHO Cells , DNA, Complementary/isolation & purification , Apoptosis Regulatory Proteins/isolation & purificationABSTRACT
La enfermedad de Alzheimer es la causa más común de demencia en la población de edad avanzada. Una de las características histopatológicas de esta enfermedad es la formación de placas seniles, cuyo componente proteínico es el péptido β-amiloide (Aβ) en su forma insoluble. Este péptido se produce normalmente en forma monomérica soluble y circula en concentraciones bajas en el líquido cefalorraquídeo y sangre. En concentraciones fisiológicas actúa como factor neurotrófico y neuroprotector, sin embargo con el envejecimiento y sobre todo en la enfermedad de Alzheimer se acumula, forma fibrillas insolubles y causa neurotoxicidad. La toxicidad del Aβ se ha asociado a la generación de radicales libres que causan peroxidación de lípidos y oxidación de proteínas entre otros daños. Se ha planteado que el Aβ pueda reconocer a receptores específicos que median a su vez neurotoxicidad. Entre estos se encuentra el receptor scavenger o pepenador que se expresa en la microglia y es capaz de internalizar agregados de este péptido. Independientemente de la vía de entrada del péptido a la célula, éste genera un estado de estrés oxidativo que eventualmente desencadena la muerte celular. Estudios recientes desarrollados en nuestro laboratorio muestran que el proceso de traducción de proteínas que intervienen en el proceso de endocitosis mediada por un receptor puede ser afectado por una condición de estrés oxidativo. Este es el caso de la β-adaptina, proteína clave en la formación del pozo cubierto.
Alzheimer's disease, the leading cause of dementia in the elderly is characterized by the presence in the brain of senile plaques formed of insoluble fibrillar deposits of beta-amyloid peptide. This peptide is normally produced in a monomeric soluble form and it is present in low concentrations in the blood and spinal fluid. At physiological concentrations, this peptide is a neurotrophic and neuroprotector factor; nevertheless, with aging and particularly in Alzheimer's disease this peptide accumulates, favors the formation of insoluble fibrils and causes neurotoxicity. beta-Amyloid peptide toxicity has been associated with the generation of free radicals that in turn promote lipid peroxidation and protein oxidation. Through the recognition of specific receptors such as the scavenger receptor, the beta-amyloid peptide becomes internalized in the form of aggregates. Independently of the way the peptide enters the cell, it generates oxidative stress that eventually triggers a state of neurotoxicity and cell death. Recent studies in our laboratory have shown the effect caused by an extracellular oxidative stress upon the internalization of the scavenger receptor. We have also demonstrated that the process of protein translation of molecules implicated in the mechanism of endocytosis through the scavenger receptor, such as the case of beta-adaptin, is arrested in microglial cells treated with beta-amyloid.
Subject(s)
Humans , Alzheimer Disease/metabolism , Peptide Fragments/metabolism , Oxidative Stress , Amyloid beta-Peptides/metabolismABSTRACT
The scavenger receptor (SRA or RPA) belongs to a wide family of receptor proteins. The classification is based on sequence homologies and structural similarities; nevertheless, it has been useful to group them on the basis of ligand specificity. The SRA was first identified as a receptor for modified low-density lipoproteins, where such modification permits to regulate the uptake of modified LDL by macrophages leading to a massive cholesterol accumulation. Moreover, SRA facilitates the clearance by phagocytic cells of microbial pathogens and senescent cells. SRA is a transmembrane glycoprotein that exists as a trimer comprised of a cystein-linker dimer and a non-covalently bound monomer. SRA has an a-helical coiled coil domain, which is essential for both trimer formation and acid-dependent ligand dissociation. It also contains a collagenous domain, essential for ligand binding. The majority of these ligands are polyanionic molecules, such as the A beta-peptide, important in the development of Alzheimer's disease. Present findings including our own consider that binding of these peptides to SRA activates an inflammatory response with the production of oxidative stress.