Regarding initialization, the activation of the ULK1 complex (ULK1/2, Atg13, FIP200 and Atg101) signals for autophagosome nucleation under the control of the PI3K III complex (PI3KIII, Beclin-1, Atg14/Barkor, Vps15 and Ambra-1), whose activation induces PIP3 (phosphatidyl inositol 3 phosphate) production, which in turn recruits other Atg proteins to form the phagophore 16. Each stage is controlled by different protein complexes regulated by the activation or inactivation of several stress-responsive pathways, such as those involving mammalian target of rapamycin (mTOR-nutrient), AMP-activated protein kinase (AMPK-energy) and hypoxia-inducible factors (HIFs-stress) 3, 15. The molecular machinery that mediates the autophagic process is evolutionarily conserved in higher eukaryotes and regulated by specific genes (ATG genes), which were initially characterized in yeast 13, 14. The degradation products include sugars, nucleosides/nucleotides, amino acids and fatty acids that can be redirected to new metabolic routes for cellular maintenance 8- 10.Īutophagy occurs at basal levels under physiological conditions and can also be upregulated in response to stressful stimuli such as hypoxia, nutritional deprivation, DNA damage, and cytotoxic agents 11, 12. Macroautophagy (herein referred to as autophagy) is the best-characterized process in this process, cytoplasmic constituents are engulfed within double-membrane vesicles called autophagosomes, which subsequently fuse with lysosomes to form autolysosomes, where the cargo are degraded or recycled 3, 7. Chaperone-mediated autophagy (CMA) recycles soluble proteins with an exposed amino acid motif (KFERQ) that is recognized by the heat shock protein hsc70 these proteins are internalized by binding to lysosomal receptors (LAMP-2A) 6. Mircroautophagy involves the direct engulfment of cargo in endosomal/lysosomal membrane invaginations 5. The specificity of the cargo and the delivery route to lysosomes distinguishes the three major types of autophagy. Autophagy is an evolutionarily conserved lysosomal catabolic process by which cells degrade and recycle intracellular endogenous (damaged organelles, misfolded or mutant proteins and macromolecules) and exogenous (viruses and bacteria) components to maintain cellular homeostasis 3, 4. The 2016 Nobel Prize in Physiology or Medicine was awarded to Yoshinori Ohsumi for his initial elucidation of the morphological and molecular mechanisms of autophagy in the 1990s 1, 2. Moreover, the possibility of using fasting as an adjuvant therapy for cancer treatment, as well as the molecular mechanisms underlying this approach, will be presented. Here, the description and role of autophagy in tumorigenesis will be summarized. Nutritional restriction is a promising protocol to modulate autophagy and enhance the efficacy of anticancer therapies while protecting normal cells. Autophagy can suppress or promote tumors depending on the developmental stage and tumor type, and modulating autophagy for cancer treatment is an interesting therapeutic approach currently under intense investigation. Dysfunctional autophagy contributes to many diseases, including cancer. Macroautophagy (herein referred to as autophagy) is a conserved lysosomal degradation pathway for the intracellular recycling of macromolecules and clearance of damaged organelles and misfolded proteins to ensure cellular homeostasis. Thus, novel therapeutic strategies to improve chemotherapy, radiotherapy and targeted therapy are an important goal in cancer research.
Although anticancer therapy has improved significantly, it still has limited efficacy for tumor eradication and is highly toxic to healthy cells. Cancer is a leading cause of death worldwide, and its incidence is continually increasing.
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