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    • Arsenic could cause apoptosis in both

    2021-04-10

    Arsenic could cause apoptosis in both benign and malignant cells (Akao et al., 2000, Gupta et al., 2003, Namgung and Xia, 2001). However, at present, little is known about the consequences of arsenic-treated urothelial cells in autophagy and expression of its related proteins. In addition, the alterations of DAPK expression and promoter methylation in urothelial cells treated with arsenic are also unclear. This prompted us to investigate the possible significances of arsenic-induced autophagy, its related protein expression, and methylation condition of DAPK gene in carcinogenesis.
    Materials and methods
    Results
    Discussion Arsenic is widely found in the earth's crust, and it is a proven toxic and carcinogenic agent, which is associated with various human malignancies, including SB505124 cancer (Steinmaus et al., 2006). Paradoxically, arsenic trioxide (As2O3) has been used successfully in the treatment of patients with newly diagnosed acute promyelocytic leukemia (APL). In vitro experiments have shown that As2O3 can exert a dual effect on APL cells: triggering apoptosis at relatively high doses (0.5–2μM) with the collapse of mitochondrial transmembrane potentials and inducing partial differentiation at low concentration (0.1–0.25μM) (Chen et al., 1997). In addition, arsenic also induced apoptosis in human urothelial cells (Somji et al., 2006), myeloma cell lines (Park et al., 2000) and solid tumors (Murgo, 2001). Recent studies showed arsenite may also induce autophagic cell death (programmed cell death type II) in malignant cells, including leukemic and malignant glioma cells (Kanzawa et al., 2003, Qian et al., 2007). However, to the best of our knowledge, there is still no report concerning arsenic-induced autophagy in normal cells. In this study, the electron microscope disclosed increase of autophagosomes in a dose-dependent manner in the arsenic-treated SV-HUC-1 cells. Therefore, we suggest that arsenic induces cell death not only via apoptosis but also autophagy in certain cell lines. The role of autophagy in the progress of cancer is still unclear. It has been shown cellular autophagic capacity is highly increased in azaserine-induced premalignant atypical acinar nodule cells (Rez et al., 1999). Autophagic capacity is found to be up-regulated in premalignant stages of the azaserine-induced tumorigenesis and down-regulated with loss of cycloheximide sensitivity of segregation with malignant transformation (Toth et al., 2001, Toth et al., 2002). In contrast, reduced autophagy in premalignant and malignant liver cells has also been reported (Ronning et al., 1981a, Ronning et al., 1981b). However, the nature of this regulation and its timing in the tumor progression in vivo remains unclear. Cells of high autophagic capacity may be prone to prompt up-regulation of their self-digesting activity in response to different extracellular signals or drugs. Generally, autophagy is suppressed during the early stages of tumorigenesis; it seems to be up-regulated during the later stages of tumor progression as a protective mechanism against stressful conditions (Cuervo, 2004a, Ogier-Denis and Codogno, 2003). Our results showed that autophagosomes was increased in a dose-dependent manner in the arsenic-treated SV-HUC-1 cells. This suggests that arsenite treatment may provide a stressful condition to the urothelial cells and cause autophagic cell death. The beclin-1 is a mammalian gene with a role in mediating autophagy (Liang et al., 1999). Moreover, it has been shown that this PI 3-kinase is required for macroautophagy in nutrient-starved cells (Eskelinen et al., 2002), for normal lysosomal enzyme sorting and protein trafficking in the endocytic pathway (Petiot et al., 2003). Beclin-1 is mono-allelically deleted in human various cancers and is expressed at reduced levels in tumors (Aita et al., 1999, Liang et al., 1999). The deletion of this region is found in up to 40% of human prostate cancers, 50% of human breast cancers, and 75% of human sporadic ovarian cancers (Aita et al., 1999, Liang et al., 1999). In vitro, Beclin-1 expression in MCF7 breast cancer cell increased the number of autophagy vesicles. The enforced expression of this autophagy gene not only promotes nutrient deprivation-induced autophagy in human breast carcinoma cells but also inhibits their tumor-forming potential, indicating that autophagy may be a fundamental mechanism for preventing the deregulated growth of tumor cells (Liang et al., 1999). On the other hand, ectopic overexpression of Beclin-1 in breast cancer cells with monoallelic deletions of the beclin-1 gene can inhibit cell proliferation, colony formation in soft agar and tumorigenesis in nude or scid mice (Furuya et al., 2005). It was indicated that Beclin-1 can function as a tumor suppressor. However, the Beclin-1 for the accumulation of autophagosomes in the initial stages of type II programmed cell death (Yu et al., 2004) suggests that its role as a tumor suppressor is most probably related to regulation of macro-autophagy.