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Conclusion
Acknowledgments
Introduction Arsenic (As) is one of the most toxic metals derived from the natural environment in soil, air and well water. It has two oxidative states: a trivalent form, arsenite, and a pentavalent form, arsenate. The inorganic As is more toxic than organic As. Arsenite is 2–10-fold more toxic than arsenate [1]. The genotoxic and co-genotoxic effects of inorganic arsenicals are well documented in mammalian systems, both in vitro[2] and in vivo[3]. The toxic effects of arsenic that are of most concern to humans are those that occur from chronic, low-level exposure. Long-term exposure to As has been associated with peripheral vascular disease, ischemic heart disease, diabetes mellitus, hypertension and various internal cancers, including skin, lung, bladder, kidney, liver and uterus. Ecological studies have demonstrated a significant dose–response relationship between arsenic concentration in well water and internal cancers [4]. The dose–response relationship between ingested arsenic from well water and erk inhibitors cancer risk has also been reported in southwestern Taiwan [5]. The bladder is particularly a target since it is the site where arsenic compounds must accumulate for excretion. Multicellular organisms have three well-characterized subfamilies of mitogen-activated protein kinases (MAPK) that control a vast array of physiological processes. The MAPK superfamily is made up of three main and distinct signaling pathways: the extracellular signaling-regulated protein kinases (ERKs), the c-Jun N-terminal kinases or stress-activated protein kinases (JNK/SAPK), and the p38 family of kinases. The MAPK cascade is a key mechanism by which such signals are transduced by the cell. The core of this cascade consists of an evolutionarily conserved module of three sequentially activated protein kinases. Catalytic activation of the MAPK requires phosphorylation on conserved tyrosine and threonine residues by a dual-specificity MAPK kinase (MAP2K/MAPKK/MEK). The EKR1/2 are activated by MAPK/ERK kinase (MEK) 1 and MEK2, which phosphorylate at the Thr-Glu-Tyr motif [6]. Many different stimuli, including growth factors, cytokines, virus infection, ligands for heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors, transforming agents, and carcinogens, can activate the ERK1/2 pathways. Autophagy from the Greek “auto” oneself and “phagy” to eat, refers to any cellular degradative pathway. Autophagy is frequently activated in response to adverse environmental conditions or stress [7], [8] and has been shown to be involved in many physiological and pathological processes, including infections, neurodegeneration, myopathies and cancers [9], [10]. Autophagy is a process where cytoplasmic material, including organelles, is segregated into a double membrane-bound vesicle and then delivered to the lysosomal compartment for degradation [11]. Autophagy is initiated by conjugation of Atg12, 5 and 8/microtubule-associated protein light chain 3 (LC3) to the nascent autophagosome membrane. During the formation of mammalian autophagosomes, two ubiquitination-like modifications are required, Atg12-conjugation and LC3-modification. The LC3 is an autophagosome ortholog of yeast Atg8, is associated to the autophagosome membranes after processing. Two forms of LC3, called LC3-I and -II. The LC3-I is cytosolic, whereas LC3-II is membrane bound [12]. The LC3-II is localized to preautophagosomes and autophagosomes, making this protein an autophagosomal marker [13]. However, the protein that is essential for autophagosome formation is Beclin-1, a 60-kDa coiled-coil protein encoded by Beclin-1 gene. It binds to Vps34, a class III PI3K, which regulate autophagosome formation [14]. In the early stage of carcinogenesis, activation of autophagy may block tumor growth, while in the late stage; it favors survival of cells in low-vascularized tumors and removal of damaged intracellular macromolecules after anticancer treatments [15]. Therefore, the role of autophagy in carcinogenesis is still uncertain.