Authors: Ropolo, Alejandro Javier; Bagnes, Claudia I.; Molejon, Maria Ines; Lo Ré, Andrea Emilia; Boggio, Veronica; Gonzalez, Claudio D.; Vaccaro, Maria Ines
Publication Date: 2011.
Language: English.
Abstract:
Autophagy is an evolutionarily preserved degradation process of cytoplasmic cellular constituents and plays important physiological roles in human health and disease. It has been proposed that autophagy plays an important role both in tumor progression and in promotion of cancer cell death, although the molecular mechanisms responsible for this dual action of autophagy in cancer have not been elucidated. Pancreatic ductal adenocarcinoma is one of the most aggressive human malignancies with 2–3% five-year survival rate. Its poor prognosis has been attributed to the lack of specific symptoms and early detection tools, and its relatively refractory to traditional cytotoxic agents and radiotherapy. Experimental evidence pointed at autophagy as a pancreatic cancer cell mechanism to survive under adverse environmental conditions, or as a defective programmed cell death mechanism that favors pancreatic cancer cell resistance to treatment. Here, we consider several phenotypical alterations that have been related to increase or decrease the autophagic process in pancreatic tumor cells. We specially review autophagy as a cell death mechanism in response to chemotherapeutic drugs.
Author affiliation: Ropolo, Alejandro Javier. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Cátedra de Fisiopatología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina
Author affiliation: Bagnes, Claudia I.. Universidad de Buenos Aires. Facultad de Medicina; Argentina
Author affiliation: Molejon, Maria Ines. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Cátedra de Fisiopatología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina
Author affiliation: Lo Ré, Andrea Emilia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Cátedra de Fisiopatología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina
Author affiliation: Boggio, Veronica. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Cátedra de Fisiopatología; Argentina
Author affiliation: Gonzalez, Claudio D.. Universidad de Buenos Aires. Facultad de Medicina; Argentina
Author affiliation: Vaccaro, Maria Ines. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Cátedra de Fisiopatología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas
Authors: Gonzalez, Claudio D.; Lee, Myung Shik; Marchetti, Piero; Pietropaolo, Massimo; Towns, Roberto; Vaccaro, Maria Ines; Watada, Hirotaka; Wiley, John W.
Publication Date: 2011.
Language: English.
Abstract:
An emerging body of evidence supports a role for autophagy in the pathophysiology of type 1 and type 2 diabetes mellitus. Persistent high concentrations of glucose lead to imbalances in the antioxidant capacity within the cell resulting in oxidative stress-mediated injury in both disorders. An anticipated consequence of impaired autophagy is the accumulation of dysfunctional organelles such as mitochondria within the cell. Mitochondria are the primary site of the production of reactive oxygen species (ROS), and an imbalance in ROS production relative to the cytoprotective action of autophagy may lead to the accumulation of ROS. Impaired mitochondrial function associated with increased ROS levels have been proposed as mechanisms contributing to insulin resistance. In this article we review and interpret the literature that implicates a role for autophagy in the pathophysiology of type 1 and type 2 diabetes mellitus as it applies to β-cell dysfunction, and more broadly to organ systems involved in complications of diabetes including the cardiovascular, renal and nervous systems.
Author affiliation: Gonzalez, Claudio D.. Hospital CEMIC; Argentina. Universidad de Buenos Aires; Argentina
Author affiliation: Lee, Myung Shik. Samsung Medical Center; Corea del Sur
Author affiliation: Marchetti, Piero. Universita Degli Studi Di Pisa; Italia
Author affiliation: Pietropaolo, Massimo. University Of Michigan; Estados Unidos
Author affiliation: Towns, Roberto. University Of Michigan; Estados Unidos
Author affiliation: Vaccaro, Maria Ines. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina
Author affiliation: Watada, Hirotaka. Juntendo University. School of Medicine; Japón
Author affiliation: Wiley, John W.. University Of Michigan; Estados Unidos
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas
Authors: Grasso, Daniel Hector; Ropolo, Alejandro Javier; Lo Ré, Andrea Emilia; Boggio, Verónica; Molejon, Maria Ines; Iovanna, Juan L.; Gonzalez, Claudio D.; Urrutia, Raúl; Vaccaro, Maria Ines
Publication Date: 2011.
Language: English.
Abstract:
Autophagy has recently elicited significant attention as a mechanism that either protects or promotes cell death, although different autophagy pathways, and the cellular context in which they occur, remain to be elucidated. We report a thorough cellular and biochemical characterization of a novel selective autophagy that works as a protective cell response. This new selective autophagy is activated in pancreatic acinar cells during pancreatitis-induced vesicular transport alteration to sequester and degrade potentially deleterious activated zymogen granules. We have coined the term “zymophagy” to refer to this process. The autophagy-related protein VMP1, the ubiquitin-protease USP9x, and the ubiquitin-binding protein p62 mediate zymophagy. Moreover, VMP1 interacts with USP9x, indicating that there is a close cooperation between the autophagy pathway and the ubiquitin recognition machinery required for selective autophagosome formation. Zymophagy is activated by experimental pancreatitis in genetically engineered mice and cultured pancreatic acinar cells and by acute pancreatitis in humans. Furthermore, zymophagy has pathophysiological relevance by controlling pancreatitis-induced intracellular zymogen activation and helping to prevent cell death. Together, these data reveal a novel selective form of autophagy mediated by the VMP1-USP9x-p62 pathway, as a cellular protective response.
Author affiliation: Grasso, Daniel Hector. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Cátedra de Fisiopatología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Author affiliation: Ropolo, Alejandro Javier. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Cátedra de Fisiopatología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Author affiliation: Lo Ré, Andrea Emilia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Cátedra de Fisiopatología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Author affiliation: Boggio, Verónica. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Cátedra de Fisiopatología; Argentina
Author affiliation: Molejon, Maria Ines. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Cátedra de Fisiopatología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Author affiliation: Iovanna, Juan L.. Inserm; Francia
Author affiliation: Gonzalez, Claudio D.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Cátedra de Fisiopatología; Argentina
Author affiliation: Urrutia, Raúl. Mayo Clinic; Estados Unidos
Author affiliation: Vaccaro, Maria Ines. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Cátedra de Fisiopatología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Keywords: AUTOPHAGY; CELL DEATH; PANCREAS; UBIQUITIN; VESICLES; PANCREATITIS; USP9x; VMP1; Patología; Medicina Básica; CIENCIAS MÉDICAS Y DE LA SALUD.
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas