Autophagy or molecular machinery for selfeating which is known as a cellular

Autophagy or molecular machinery for self-eating, which is known as a cellular process, can reveal different clinical responses in various diseases such as cancer and non-cancerous disorders. In recent years; research on the autophagic process has greatly increased. By studying this molecular process, several markers and strategies have been reported in different biological systems in both in vivo and in vitro conditions. Similarly, mechanisms of heavy metal-induced toxicity remain important given the ubiquitous nature and distribution of these contaminants in the environment.

Among the environmental pollutants arsenic (As) has attracted more attention. Inorganic arsenic is a confirmed carcinogen and is the most significant chemical contaminant in drinking-water globally. Despite the fact due to exposure to arsenic, there are harmful effects in human, but arsenic trioxide [As2O3 (ATO)] has important antitumor properties; so this study is aimed to comprehensively review all available literature about the role of autophagy in the exposure with various forms of arsenic. 1.1. By cleansing and removing damaged organelles, autophagy plays an important role in controlling cell cytoplasm and causes protein aggregates through pathways integrating with lysosomes (1, 2).

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To date, macroautophagy (dominant path), microautophagy, and chaperone-mediated autophagy have been identified as three main types of autophagy (3, 4). By inhibiting the mammalian target of rapamycin (MTOR) when cells require nutrient and energy production, autophagy is upregulated. Autophagy is implemented by producing evolutionary protein products (originally identified in yeasts) called autophagy-related (ATG) genes and proteins, which are essential for isolating the membrane and autophagosomes, and their formation consists of three main steps as described in the figure.

Elongating and isolating membrane is mainly affected by starting with the complex of uncoordinated 51-like kinase 1(ULK1), nucleation with the Beclin-1-class III phosphatidylinositol 3-kinase (PI3K) complex and microtubule-associated protein light chain 3 (LC3) (5-7). 1.2.3. Arsenic as a public, environmental and industrial contaminant discrete worldwide may be present in the well water or food (10). Due to arsenic-contaminated drinking water from natural sources, environmental arsenic exposure mostly happens. In Mexico, Argentina, China, Bangladesh, India, and Iran, many people consumed arsenic-contaminated drinking water (11)(REF?). Drinking arsenic-contaminated groundwater leads to various pathological conditions such as dermal lesions, hypertension, liver disease, neuropathy, and cancer (1). While exposure to arsenic has harmful effects in human, arsenic trioxide has important antitumor properties (ref?). The role of arsenic and its metabolites in oxidative DNA damage, alteration in DNA methylation status and genomic instability, repairing impaired DNA damage, as well as enhanced cell proliferation or cell death is proven (9). An oxidative decline of polyunsaturated fatty acids by a procedure, which has been recognized as lipid peroxidation, has been frequently accepted as a general apparatus of action for cellular damage and toxic properties of arsenic (13-15). It is well informed that the chief cause of genotoxicity in laboratory animals is arsenic-induced lipid peroxidation and generation of reactive oxygen species (16-18). However, according to recent studies, there is a possibility that arsenic may have a different mechanism with what has been said so far. Autophagy is a cell death mechanism distinct from apoptosis, also defined as type II programmed cell death, involving autophagosomal/lysosomal degradation of cellular components (9 (. Effect of arsenic in regulating autophagy depends on the type of cells and cellular stress. To date, a lot of studies have been carried out on arsenic-induced changes in autophagy pathways (19-26). Meanwhile, arsenic role as a therapeutic or toxigenic agent and its relevance to this pathway has been discussed (27-33). As such, proper understanding of how this interferes with the occurrence and treatment of disease requires an appropriate assessment of the findings.3.1.Autophagy alterations happen in various diseases, for instance, cancer and non-cancerous disorders (35-43). The studies indicate that arsenic's role in regulating autophagy depends on dose and duration of exposure, type of cells and cellular stress. To this point, cytoprotective or toxic effects of arsenic-induced changes in autophagy pathways have been investigated by many studies. So in this systematic review, we summarize the relationship of autophagy with cancer and non-cancerous disorders in arsenic exposure or treatment.3.1.1. Autophagy has a dual role as a tumor suppressor and a tumor promoter in the presence of cancer cells. Due to over proliferation, cancer cells have high levels of cellular metabolism (44). Taking into account the fact that growing cancer cells necessitates energy , the level of autophagy will be increased by these cells (45). In addition, in order to maintain cellular biosynthesis and survival under the cytotoxic and metabolic stresses such as hypoxia and nutrient deprivation, which occur in cancer, autophagy is activated. It has been claimed that autophagy in hypoxic tumor cells is induced in regions that are distal to the blood vessels. The induction of autophagy is sometimes in association with the hypoxia-inducible factor-1± (HIF-1±), increasing the expression of factors involved in angiogenesis, including vascular endothelial growth factor, platelet-derived growth factor and nitric oxide synthase (46). After doing chemotherapy or radiation, increased autophagy surviving in cancer cells can lead to dormancy in resistant cancer cells or tumor recurrence. Therefore, the efficacy of anticancer drugs can be increased by inhibiting autophagy in tumor cells (47). Conversely, defects in autophagy can lead to the accumulation of Sequestosome 1 (SQSTM1) also called p62 proteins, damaged mitochondria and misfolded proteins, reactive oxygen species (ROS), and finally, damage to DNA and genomic instability (44). The Beclin-1 protein [mammalian ortholog of the yeast autophagy-related gene 6 (Atg6)], required for the induction of autophagy, is a haploinsufficient tumor suppressor gene. The stimulation of autophagy following the increased expression of this gene can lead to tumor development inhibition (48). Furthermore, autophagy can protect against tumor genesis by controlling the proinflammatory, factor-induced chronic necrosis and inflammation called HMGB1. Cell death is associated with no less than three morphologically distinct processes that have been named apoptosis, necrosis and autophagic cell death (ACD). By giving the cell a characteristic vacuolated appearance, ACD is characterized by the large-scale sequestration of portions of the cytoplasm in autophagosomes. Additionally, it has been proposed that depending on the cell type and genetic background in conjunction with anticancer drugs, induction of autophagic cell death can be used to improve cancer treatments (?). According to evidence from human studies that reported arsenic creates cancers such as the lung, bladder, and skin, an agency affiliated to the World Health Organization (WHO), known as the International Agency for Research on Cancer (IARC), classifies arsenic and its inorganic compounds as carcinogenic to humans (?). On the other hand, since ancient times, arsenical drugs have been used and even today, they are very efficient against acute promyelocytic leukemia. According to many studies, the antitumor mechanism of arsenic is very complicated and it may result from causing cell cycle arrest and inducing tumor cell apoptosis. Recent studies have demonstrated that ATO induced autophagy in several kinds of cancer cells, however; the detailed mechanisms of arsenic-mediated cell death is not fully understood. (49-52). Therefore, considering the dual role of arsenic and autophagy in the induction and treatment of cancer, it seems that collecting and reviewing information in this field is necessary to achieve therapeutic or preventive goals.3.1.1.1 So far, autophagy role in ATO anticancer effects on human acute promyelocytic leukemia NB4 cells repeatedly is studied (59-62). Autophagy modification augmented the treatment effects of ATO in NB4 cells. ATO treatment causes proteolytic degradation of a highly oncogenic protein, the PML/RARA fusion protein that sustains malignant transformation supporting concomitant disease remission, demonstrating the catabolism of PML/RARA is largely affected also by this protein degradation pathway and that the clearance of this oncoprotein correlates with increased autophagic activity (61, 62).The HL-60 cell line, which is derived from a single patient with acute promyelocytic leukemia, is responsible for a unique in vitro model system for studying the cellular and molecular events involved in proliferating and differentiating normal and leukemic cells of the granulocyte/monocyte/macrophage lineage (ref? blood). In a study, the cytotoxic effects of inorganic and methylated arsenical species in HL-60 cells with the aim of determining the mode(s) of cell death induced by arsenicals investigated and, according to transmission electron microscope (TEM), acridine orange binding, and LC-3 marker assays no evidence of autophagy was reported (55) although YP Yang et al. (63) and also L Yang et al. reported that arsenic trioxide-induced autophagic cell death in HL-60 cells (64). ATO significantly inhibited the proliferation of Raji cells in a dose and time-dependent manner. Raji is the first continuous human cell line of hematopoietic origin1 and was derived almost over forty years ago from a Nigerian patient with Burkitt's lymphoma (BL). ATO in Raji cells induced G2/M phase cell cycle arrest and apoptosis. Moreover, ATO also promoted the formation of autophagic vacuoles, as well as increased the degradation of autophagy substrate P62 protein, which was accompanied by an upregulation of Beclin1 gene and downregulation of Bcl2 gene expression(49, 65). In a study alongside ATO treatments blocking ROS production with antioxidants or ROS scavengers effectively inhibits cell death and autophagy formation in U937 (human histiocytic lymphoma cell line) and BM2 (V-myb-transformed chicken BM2 monoblasts) cell lines respectively this result indicating that ROS may participate in the induction of apoptosis of U937 and autophagy of BM2 cells treated with ATO (70). Exposure of U937 cells to arsenite promotes superoxide formation and inhibition of the activity of aconitase, an O2°- sensitive enzyme. Arsenite selectively triggers events associated with the mitochondrial formation of O2°-. These radicals dismutate to H2O2, presumably in the mitochondria, in which the oxidant produces damage through the intermediate formation of hydroxyl radical species. Part of the H2O2 produced exits the mitochondria, thereby triggering autophagy and downstream events fostering the mitochondrial dysfunction. Mitochondrial permeability transition pore (MPT) resulting from either direct effect of intramitochondrial H2O2, or by these effects combined with autophagy, subsequently leads to apoptosis (71). K562 cells is a human chronic myelogenous leukemia (CML) cell line that is established from a patient in a blast crisis of chronic myeloid leukemia and possesses variable capacities of differentiation toward erythroid and megakaryocytic cell lineages (72). Recently, Isakson et al. reported that autophagy is essential for differentiation therapy of CML patients and could be activated by chemotherapeutic drugs in leukemia cell lines (62). ATO efficacy on differentiation, proliferation, apoptosis, autophagy, self-renew, and senescence is associated with dose used in K562 cells and their initiating cells (K562s). K562s cells are stronger in self-renew and resistance to ATO cytotoxicity and starvation-induced apoptosis than K562 cells. The optimal dose of ATO shows opposite efficacy on autophagy between K562 and their initiating cells and ultimately leads both cells to late-phase senescence(75). ATO is a potent inducer of autophagy in K562 and also in its drug-resistant line K562/ADM cells. Reduction in the expression level of Bcl-2 gene, suggesting that maybe Bcl-2 involved in the accumulation of Beclin-1 and triggering autophagic cell death in ATO-treated K562 leukemia cells (76). Several molecular mechanisms are participating in the efficacy of arsenic trioxide against malignant hematologic and some solid tumors. FLICE-like inhibitory protein (FLIP) as an inhibitor of apoptosis is mediated by death receptors. A new link between the down-regulation of cellular FLIPL and ATO-induced autophagy has been identified In a study. ATO induced the FLIPL degradation in the K562 and MGC803 cells, which was mediated by the ubiquitin-proteasome pathway. Moreover, the Casitas B-lineage lymphoma-b (Cbl-b) is involved in this process, which interacted with FLIPL and promoted proteasomal degradation of FLIPL (77). Cbl-b belongs to the single-protein RING family of ubiquitin ligases, and the RING-finger domain serves to recruit ubiquitin-loaded E2 and bind tyrosine kinases through its N-terminal tyrosine kinase binding domain. Multiple substrates, specifically those related to T cell receptor (TCR) activation and signaling, have been described for Cbl-b, including protein kinase C (PKC), phospholipase C1, Vav-1, and the p85 subunit of phosphatidylinositol 3-kinase (PI3K-p85). In particular, the role of ubiquitin or E3 ligases, such as Cbl-b, gene-related anergy in lymphocytes (GRAIL), and Itch, as negative regulators of the immune response has been well characterized. These E3 ligases as components of the anergy-induced genetic program that can be modulated by the calcium/calcineurin pathway (REF?). According to some evidence, arsenic trioxide targets the BCR-ABL oncoprotein by a novel mechanism including p62/SQSTM1. p62/SQSTM1 mediated localization of the oncoprotein to the autolysosomes and subsequent degradation by the protease cathepsin B. Inhibitors of autophagy or activity of cathepsin B and/or molecular targeting of p62/SQSTM1, Atg7 and cathepsin B cause A partial reversal of the suppressive effects of ATO on BCR-ABL expressing leukemic progenitors (78). It is demonstrated that realgar (As4S4) nanoparticles also can inhibit the proliferation of K562 cells and degrade BCR-ABL fusion protein effectively while the underlying mechanism might be related to apoptosis and autophagy. The induction of autophagy by realgar nanoparticles is associated with class I phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathway (79). Data demonstrate that ATO is a potent inducer of autophagy in AML, and such induction is mediated by engagement of the MEK/ERK pathway. Importantly, these findings establish that pharmacological or molecular targeting of proteins involved in arsenic-mediated autophagy results in partial reversal of the anti-leukemic effects of ATO on primary hematopoietic precursors (80). In the human T-lymphocytic leukemia cell line Molt-4, ATO induces autophagy through the up-regulation of Beclin-1 as an additional mechanism to apoptosis. Bax may be involved in accumulating of Beclin-1 and triggering autophagic cell death in ATO-treated leukemia cells (81).