HACER KARAKAŞ - Academia.edu (original) (raw)

Papers by HACER KARAKAŞ

TURKISH JOURNAL OF BIOLOGY, 2014

Introduction Autophagy is a basic cellular event conserved in all eukaryotes from yeast to man. I... more Introduction Autophagy is a basic cellular event conserved in all eukaryotes from yeast to man. It serves as an intracellular quality-control mechanism recycling long-lived or misfolded/aggregate-prone proteins and damaged organelles, such as mitochondria. Moreover, under stress conditions, autophagy is upregulated in order to generate building blocks that are necessary for cellular survival (Kuma and Mizushima, 2010; Rabinowitz and White, 2010). Therefore, autophagy mainly serves as a stress-adaptation and survival mechanism (Su et al., 2013). However, under certain conditions, autophagy was reported to contribute to programmed cell death either indirectly through crosstalk mechanisms with apoptosis (Gozuacik and Kimchi, 2004; Oral et al., 2012; Rubinstein and Kimchi, 2012) or directly through autophagic cell death (Gozuacik and Kimchi, 2007). Abnormalities of autophagy were reported in various diseases, including neurodegenerative diseases, lysosomal storage diseases, infections, metabolic diseases, and ischemia/reperfusion injury (Schneider and Cuervo, 2014). Cancer is no exception. The roles of autophagy in cancer formation, growth, ischemia resistance, metabolic changes, neovascularization, and even metastasis and tumor dormancy were reported (Gewirtz, 2009; Guo et al., 2013b; Murrow and Debnath, 2013). Moreover, autophagic capacity was shown to significantly affect responses of cancer cells to anticancer agents and radiation (Eberhart et al., 2013). In this review we will mainly focus on the role of autophagy in cancer formation and cancer therapy. 2. Basic mechanisms of autophagy There are 2 major catabolic mechanisms in mammalian cells: the ubiquitin-proteasome system and the autophagylysosomal system. Proteasomes degrade mainly shortlived and soluble proteins following their regulated ubiquitinylation (Hershko and Ciechanover, 1998). In contrast, lysosomal pathways rely on the delivery of cytosolic contents into the lumen of the organelle, an event that is followed by their degradation by specific hydrolases. Here, ingested cytoplasmic targets might be various. The list includes long-lived proteins, old and damaged organelles (e.g., mitochondria and peroxisomes); misfolded, mutant, and/or aggregated proteins; and pathogens such as bacteria, viruses, and parasites. So far, 3 subtypes of autophagy have been described in mammals: microautophagy, chaperone-mediated autophagy (CMA), and macroautophagy (Klionsky and Schulman, 2014). Microautophagy proceeds through direct invagination of the vacuolar/lysosomal membrane and engulfment of nearby cytosolic materials (Uttenweiler et al., 2005). In addition to cargo digestion, microautophagic vacuoles also contribute to the maintenance of organelle size and membrane composition (Mijaljica and Devenish, 2011).

TURKISH JOURNAL OF BIOLOGY, 2014

Introduction Autophagy is a basic cellular event conserved in all eukaryotes from yeast to man. I... more Introduction Autophagy is a basic cellular event conserved in all eukaryotes from yeast to man. It serves as an intracellular quality-control mechanism recycling long-lived or misfolded/aggregate-prone proteins and damaged organelles, such as mitochondria. Moreover, under stress conditions, autophagy is upregulated in order to generate building blocks that are necessary for cellular survival (Kuma and Mizushima, 2010; Rabinowitz and White, 2010). Therefore, autophagy mainly serves as a stress-adaptation and survival mechanism (Su et al., 2013). However, under certain conditions, autophagy was reported to contribute to programmed cell death either indirectly through crosstalk mechanisms with apoptosis (Gozuacik and Kimchi, 2004; Oral et al., 2012; Rubinstein and Kimchi, 2012) or directly through autophagic cell death (Gozuacik and Kimchi, 2007). Abnormalities of autophagy were reported in various diseases, including neurodegenerative diseases, lysosomal storage diseases, infections, metabolic diseases, and ischemia/reperfusion injury (Schneider and Cuervo, 2014). Cancer is no exception. The roles of autophagy in cancer formation, growth, ischemia resistance, metabolic changes, neovascularization, and even metastasis and tumor dormancy were reported (Gewirtz, 2009; Guo et al., 2013b; Murrow and Debnath, 2013). Moreover, autophagic capacity was shown to significantly affect responses of cancer cells to anticancer agents and radiation (Eberhart et al., 2013). In this review we will mainly focus on the role of autophagy in cancer formation and cancer therapy. 2. Basic mechanisms of autophagy There are 2 major catabolic mechanisms in mammalian cells: the ubiquitin-proteasome system and the autophagylysosomal system. Proteasomes degrade mainly shortlived and soluble proteins following their regulated ubiquitinylation (Hershko and Ciechanover, 1998). In contrast, lysosomal pathways rely on the delivery of cytosolic contents into the lumen of the organelle, an event that is followed by their degradation by specific hydrolases. Here, ingested cytoplasmic targets might be various. The list includes long-lived proteins, old and damaged organelles (e.g., mitochondria and peroxisomes); misfolded, mutant, and/or aggregated proteins; and pathogens such as bacteria, viruses, and parasites. So far, 3 subtypes of autophagy have been described in mammals: microautophagy, chaperone-mediated autophagy (CMA), and macroautophagy (Klionsky and Schulman, 2014). Microautophagy proceeds through direct invagination of the vacuolar/lysosomal membrane and engulfment of nearby cytosolic materials (Uttenweiler et al., 2005). In addition to cargo digestion, microautophagic vacuoles also contribute to the maintenance of organelle size and membrane composition (Mijaljica and Devenish, 2011).