This collection of membranes serves as a platform to which the various so-called proteins derived from autophagy-related genes (ATGs) are then recruited. This finding gains particular significance as p53 deficiency or mutant variants of p53 that accumulate in the cytoplasm of tumor cells enable activation of autophagy. Accordingly, we recently identified p53 as a molecular hub that regulates autophagy and apoptosis Praziquantel (Biltricide) in histone deacetylase inhibitor-treated uterine sarcoma cells. In light of this novel experimental evidence, in this review, we focus on p53 signaling as a mediator of the autophagic pathway in tumor cells. strong class=”kwd-title” Keywords: p53, mTOR, autophagy, histone deacetylase inhibitor, suberoylanilide hydroxamic acid, tumor 1. Introduction: Autophagy and Tumorigenesis Autophagy is a self-degradative process that represents an important physiological catabolic mechanism of the eukaryotic cell. Thereby, organized degradation and recycling of non-functional or non-required cellular components as a reaction to changing conditions is enabled [1,2,3]. The different pathways of autophagy have been classified into three categories: macroautophagy, microautophagy, and chaperone-mediated autophagy [4,5,6,7]. Via lysosomal degradation, basic macroautophagy, to which we Rabbit Polyclonal to CES2 refer in this review, allows, in addition to the proteasome-mediated pathway, the turnover of long-lived protein and organelles, the maintenance of anabolicCcatabolic homeostasis, the counteraction of aging, and the preservation of energy of the cell. Thereby, autophagy together with apoptosis is also granted a crucial role in cellular quality control . Furthermore, autophagy is particularly indispensable for the cell in its response to nutrient starvation and other types of stressful conditions . Autophagy is encountered during embryonic development and cell differentiation and participates in the innate immune response by eliminating invading intracellular bacteria and viruses. In 2016, the Nobel Prize in Physiology or Medicine was awarded to Yoshinori Ohsumi for his groundbreaking experiments related to the mechanisms of autophagy in starvation-induced non-selective autophagy [1,9,10,11]. Selective autophagy describing the cytoplasm-to-vacuole targeting (CVT) pathway was discovered a few years later by Daniel J. Klionskys group . Although the process of autophagy was discovered half a century ago and the term autophagy derived from the ancient Greek meaning for self-eating was given by the Belgian biochemist Christian de Duve in 1963, its fundamental importance as a physiological cellular mechanism was only appreciated upon Ohsumis research in yeast in the 1990s . Subsequently, as autophagy is conserved throughout evolution, the corresponding autophagic machinery involved in its Praziquantel (Biltricide) pathway has been discovered in all eukaryotes, including humans . Autophagosomal dysfunction can be caused by genetic mutations that have been associated with the pathogenesis of diseases such as the neurodegenerative Parkinsons disease, type 2 diabetes, and cancer . Thus, ongoing research is focused on the development of drugs that can target autophagy in these specific diseases. The role of autophagy in cancer offers high potential for future therapy and is, therefore, currently also intensively investigated. Different from apoptotic or necrotic programmed cell death, autophagy can pursue either a pro-survival or a pro-death strategy if mediated in tumor cells [15,16]. Specifically, encountered often in apoptosis-resistant tumor cells, autophagy takes on a tumor suppressive function, which limits tumor necrosis and inflammation . In this context, autophagy may be regarded as a protective pro-survival mechanism that inhibits the onset of apoptotic and necrotic cell death in a concerted action [15,18,19,20,21]. Moreover, it can help tumor cells deal with metabolic stress and overcome the cytotoxicity of chemotherapy. In cells and conditions where autophagy may have a supportive function in cell death, however, unelucidated mechanisms seem to expedite the autophagic program . Inhibition of Praziquantel (Biltricide) autophagy in tumor cells will, therefore, promote tumor survival. Praziquantel (Biltricide) Alternatively, tumor cells could capitalize on autophagy for their survival due to the higher turnover requirements of their metabolism. Regardless of these facts, disruption of autophagy in combination with chemotherapeutic treatment has been approached intensively in cancer therapy. Praziquantel (Biltricide) For these reasons there is certainly a lack of knowledge about autophagic signaling in tumor cells. As a consequence, before determining whether autophagy interference can be applied in tumor therapy and a better clinical translation of basic research findings in the future, it is even more important and desirable to first define and gather molecular clues that confirm the context-dependent role of autophagy in tumorigenesis [23,24,25]. 2. The Cellular Mechanism of Autophagy During the process of macroautophagy, the controlled formation of a vesicle with a bilayer membrane is initiated allowing the separation of targeted cellular components or organelles from the rest of the cytoplasm . This vesicle, known as.
This collection of membranes serves as a platform to which the various so-called proteins derived from autophagy-related genes (ATGs) are then recruited
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