如同大多數的砷化物，偏亞砷酸鈉 (sodium arsenite, NaAsO2) 也被認為是一種致癌物與環境汙染物。除了造成氧化壓力與細胞生理異常，NaAsO2誘導許多壓力相關基因的表現，例如在金屬解毒與避免細胞遭受氧化壓力中扮演重要角色的金屬硫蛋白 (metallothionein, MT) 便會受砷誘導表現 。本研究中我們使用兩種MT基因表現差異的中國倉鼠卵巢細胞 ，分別為MT基因不被誘導的CHO-K1和被大量誘導表現Cdr細胞，探討NaAsO2誘發的細胞毒性。兩種細胞以NaAsO2處理都會降低細胞存活率並且增加Sub-G1比例。NaAsO2增加caspase-3活性，造成CHO-K1細胞凋亡，而此現象可被pan-caspase的抑制劑z-VAD-fmk所抑制；然而Cdr的細胞凋亡則非經由caspase相關的路徑。此外NaAsO2也會造成細胞自噬，我們發現Cdr細胞會完成細胞自噬過程；然而在CHO-K1中NaAsO2誘發的細胞自噬過程會被阻斷，並發現autophago-somes的累積，LC3-II與p62的增加，以及溶酶體酸性磷酸酶活性的下降。當進一步以細胞自噬的抑制劑3-MA處理後會減少autophagosome的形成，並且降低NaAsO2造成的細胞死亡，因此我們認為在CHO-K1中細胞自噬為走向死亡的機制，但我們仍不清楚細胞自噬在Cdr細胞中扮演的角色。當處理ROS清除物N-acetylcysteine之後， NaAsO2所造成的兩種細胞死亡都會降低，顯示砷之細胞毒性與ROS相關。降低Cdr細胞中MT的表現會使得ROS含量增加，並加劇NaAsO2誘發細胞死亡，表示MT參與防禦砷之毒性。我們的結果顯示MT基因不受誘導表現的CHO-K1細胞中，NaAsO2會造成caspase相關的細胞凋亡，並且阻礙細胞自噬過程；然而MT基因大量表現的Cdr細胞凋亡則與caspase無關，並且細胞自噬也不受影響。而MT基因表現的差異性，可能保護細胞對抗砷透過ROS造成的細胞毒殺。 

Like other inorganic arsenicals, sodium arsenite (NaAsO2) is recognized as a human carcinogen and environmental pollutant. In addition to induction of oxidative stress and cellular abnormalities, sodium arsenite induces expression of multiple stress response genes, including metallothionein (MT), which plays a crucial role in metal detoxification and oxidative stress protection.
Here, we investigated sodium arsenite-induced toxicity in MT quiescent and over-expressed Chinese hamster ovary cells (CHO-K1 and Cdr cells, respectively). Sodium arsenite reduced cell viability and increased Sub-G1 population in both CHO-K1 and Cdr cells. The apoptosis induced by sodium arsenite in CHO-K1 cells was correlated with increased caspase-3 activity, and was partially inhibited by the pan-caspase inhibitor z-VAD-fmk. However, the apoptotic death in Cdr cells was through caspase-independent mechanisms. Sodium arsenite enhanced autophagy in both CHO-K1 and Cdr cells. Noticeably, the autophagic flux was completely progressed in Cdr cells, but was blocked in CHO-K1 cells. Arsenic treatment caused an accumulation of autophagosomes, elevation of LC3-II and p62, and decrease of lysosomal acid phosphatase activity in CHO-K1 cells, but not in Cdr cells. The autophagy may serve as a pro-death mechanism in CHO-K1 cells since inhibition of autophagosome formation by 3-methyladenine potentially diminished cell death caused by sodium arsenite. Nonetheless, the impact of autophagy on the cell fate of Cdr cells cannot be defined presently. Administration of N-acetylcysteine, a ROS scavenger, attenuated sodium arsenite-triggered cell death in both CHO-K1 and Cdr cells, indicating that sodium arsenite-induced toxicity was ROS-dependent. Finally, downregulation of MT expression increased ROS production and exacerbated sodium arsenite-triggered cell death in Cdr cells. This result suggested the involvement of MT in cellular defense system against arsenite toxicity.
In conclusion, our results revealed that sodium arsenite induced caspase-dependent apoptosis, and inhibited autophagic flux in CHO-K1, whereas it triggered caspase-independent apoptosis and facilitated a complete autophagic flux in Cdr cells. Moreover, differential expressions of MTs in CHO-K1 and Cdr cells may be involved in protecting cells against ROS-dependent cell death induced by arsenite.

ABSTRACT 3
ABBREVIATIONS 1
1.1. Metallothioneins 6
1.2. Reactive oxygen species 9
1.3. Apoptosis 11
1.4. Autophagy 15
1.5. Sodium arsenite 19
Chapter 2 MATERIALS AND METHODS 21
2.1. Cell culture and chemicals 21
2.2. Cell viability assay 22
2.3. Preparation of whole cell lysates 22
2.4. Immunoblotting analysis 22
2.5. Immunofluorescence analysis 23
2.6. Cell cycle analysis 23
2.7. Caspase-3 activity assay 24
2.8. Acid phosphatase activity assay 24
2.9. Measurement of intracellular ROS 24
2.10. siRNA transfection 25
2.11. Total RNA extraction and quantitative real-time PCR 25
2.12. Statistical analysis 26
Chapter 3 RESULTS 27
3.1. Cdr cells exhibit over-expressed level of MT-2A protein and enhanced cadmium resistance potential 27
3.2. Sodium arsenite inhibits cell proliferation and induces cell death in both CHO-K1 and Cdr cells 28
3.3. Sodium arsenite triggers caspase-dependent apoptosis of CHO-K1 cells, but caspase-independent cell death in Cdr cells 29
3.4. Sodium arsenite activates autophagy in Cdr cells, but instead blocks autophagic flux in CHO-K1 cells 30
3.5. Sodium arsenite damages cells via ROS-dependent mechanisms 31
3.6. Metallothionein may be involved in cellular defense mechanisms against sodium arsenite-induced cell death 32
Chapter 4 DISCUSSION 35
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