m-3M3FBS能夠刺激細胞內鈣離子濃度的上升，且細胞內鈣離子濃度的上升是經由PLC (Phosphoinositide-specific phospholipase C)的活化路徑來完成，由於PLC常常參與在各種不同細胞的細胞訊息傳遞反應過程中，因此這種刺激作用是否一樣適用於腎臟MDCK細胞以及口腔癌OC2細胞，仍未可知。所以我們將利用鈣離子敏感的螢光染料fura-2來探討m-3M3FBS對於腎臟MDCK細胞以及口腔癌OC2細胞活化PLC的分子機轉，以及PLC調節的細胞訊息傳遞的相關作用。我們發現0.1-20 μM m-3M3FBS會造成MDCK細胞內鈣離子濃度的上昇，而且細胞內鈣離子濃度會隨著藥物濃度的升高而上昇，然而在OC2細胞，m-3M3FBS的濃度須達到10-60 μM才會造成細胞內鈣離子濃度的上昇；當移除細胞外鈣離子，會稍微降低m-3M3FBS造成的細胞內鈣離子濃度上昇，表示細胞內鈣離子濃度的上昇有一部分是因為細胞外鈣離子的流入，而這種細胞外鈣離子的流入會受到鈣離子通道抑制劑nifedipine、econazole、SK&F96365以及phospholipase A2抑制劑aristolochic acid的影響。於無鈣溶液中，經由m-3M3FBS前處理的細胞，會完全抑制內質網鈣離子幫浦抑制劑（例如thapsigargin、cyclopiazonic acid 或者2,5-di-tert-butylhydroquinone (BHQ)）引起之細胞內鈣離子上升，相反的，利用thapsigargin、cyclopiazonic acid 或者BHQ前處理的細胞，會部份抑制m-3M3FBS作用所引起之細胞內鈣離子上升，而且m-3M3FBS造成的細胞內鈣離子的釋放不會因為PLC的抑制劑U73122的作用而改變。總之，研究結果顯示，m-3M3FBS誘發MDCK和OC2細胞內鈣離子濃度的增加，是經由與PLC無關的內質網鈣離子通道釋放而來，以及store-operated鈣離子通道的流入，還有尚未確定發現的鈣離子通道所共同影響。除了鈣離子濃度的變化，我們發現m-3M3FBS濃度介於5至100 μM 時，其毒殺OC2細胞的能力與濃度呈正比，且細胞內鈣離子敖合劑1,2-bis(2-aminophenoxy)ethane- N,N,N',N'-tetraacetic acid (BAPTA) 並不會抑制m-3M3FBS的細胞毒殺效用。Propidium iodide螢光染色的流體細胞實驗測定發現20 μM及50 μM的m-3M3FBS會誘發與鈣離子無關的細胞凋亡。
由實驗的結果知道m-3M3FBS會誘發與鈣離子無關的細胞凋亡，但是這與其他人發表的研究結果有所不同，因此我們也有興趣得知細胞內鈣離子敖合劑BAPTA是否也能抑制氧化壓力造成的MDCK細胞的死亡，以及這樣的死亡過程是否與m-3M3FBS誘發與鈣離子無關的細胞凋亡相同。我們發現BAPTA能夠抑制tBHP和H2O2誘發的細胞死亡，而且BAPTA的濃度愈高抑制細胞死亡的效果愈好，因此我們推測tBHP和H2O2誘發的MDCK細胞死亡是與鈣離子相關的細胞死亡。接著我們利用2 μM U73122 (PLC抑制劑)、50 μM zVAD-fmk (caspase抑制劑)、2 μM cyclosporin A (MPTP抑制劑)、20 μM PD98059 (ERK抑制劑)、2 μM SP600125 (JNK抑制劑)…等，都沒有發現能夠抑制tBHP和H2O2誘發的MDCK細胞死亡，推測tBHP和H2O2誘發的MDCK細胞死亡並不是經由PLC, MPTP, caspase, ERK或者JNK的路徑。從propidium iodide螢光染色、caspase-3活性分析以及倒立顯微鏡下的細胞形態的結果讓我們認為tBHP和H2O2誘發的MDCK細胞死亡並不是走細胞凋亡的路徑，它比較像是細胞壞疽，而且是caspase無關、鈣離子相關的細胞死亡。
抗憂鬱藥物paroxetine對於人類口腔癌細胞OC2細胞內鈣離子細胞訊息傳遞的作用仍未可知，因此我們也利用鈣離子敏感的螢光染料fura-2來探討paroxetine對於口腔癌OC2細胞內調節鈣離子濃度的相關作用。我們發現100-1000 μM paroxetine會造成OC2細胞內鈣離子濃度的上昇，而且細胞內鈣離子濃度會隨著藥物濃度的升高而上昇；當移除細胞外鈣離子，會降低50%左右的paroxetine造成的細胞內鈣離子濃度上昇，表示細胞內鈣離子濃度的上昇有50%是因為細胞外鈣離子的流入，而這種細胞外鈣離子的流入會受到鈣離子通道抑制劑nifedipine、econazole、SK&F96365、phospholipase A2抑制劑aristolochic acid以及蛋白質激酶C的影響而被抑制。於無鈣溶液中，經由內質網鈣離子幫浦抑制劑thapsigargin前處理的細胞，會完全抑制paroxetine造成OC2細胞內鈣離子濃度上昇的作用，而且paroxetine造成的細胞內鈣離子的釋放不會因為PLC的抑制劑U73122的作用而改變。除了鈣離子濃度的變化，我們發現paroxetine濃度介於10至50 μM 時，其毒殺OC2細胞的能力與濃度呈正比，且細胞內鈣離子敖合劑BAPTA並不會抑制paroxetine的細胞毒殺效用。Propidium iodide螢光染色的流體細胞實驗測定發現paroxetine會誘發與鈣離子無關的細胞凋亡。總之，研究結果顯示，paroxetine誘發OC2細胞內鈣離子濃度的增加，是經由與PLC無關的內質網鈣離子通道釋放而來，以及phospholipase A2和蛋白質激酶C有關的store-operated鈣離子通道的流入，至於paroxetine造成的細胞死亡是與鈣離子無關的細胞凋亡作用。

The effect of 2,4,6-trimethyl-N-(meta-3-trifluoromethyl-phenyl)- benzenesulfonamide (m-3M3FBS), a presumed phospholipase C activator, on cytosolic free Ca2+ concentrations ([Ca2+]i) in Madin Darby canine kidney (MDCK) cells and OC2 human oral cancer cells was unclear. This study explored whether m-3M3FBS changed basal [Ca2+]i levels in suspended MDCK and OC2 cells by using fura-2 as a Ca2+-sensitive fluorescent dye. m-3M3FBS at concentrations between 0.1-20 μM increased [Ca2+]i in a concentration-dependent manner in MDCK cells, however in OC2 cells, m-3M3FBS at concentrations between 10-60 μM increased [Ca2+]i in a concentration-dependent manner. The Ca2+ signals were reduced partly by removing extracellular Ca2+ in the two cell types. m-3M3FBS-induced Ca2+ influx was inhibited by the store-operated Ca2+ channel blockers nifedipine, econazole and SK&F96365, and by the phospholipase A2 inhibitor aristolochic acid. In Ca2+-free medium, m-3M3FBS pretreatment abolished the [Ca2+]i rise induced by the endoplasmic reticulum Ca2+ pump inhibitors thapsigargin, cyclopiazonic acid or 2,5-di-tert-butylhydroquinone (BHQ). Conversely, pretreatment with thapsigargin, cyclopiazonic acid or BHQ partly reduced m-3M3FBS-induced [Ca2+]i rise. Inhibition of phospholipase C with U73122 did not alter m-3M3FBS-induced [Ca2+]i rise. Collectively, in MDCK and OC2 cells, m-3M3FBS induced [Ca2+]i rises by causing phospholipase C-independent Ca2+ release from the endoplasmic reticulum and Ca2+ influx via store-operated Ca2+ channels and other unidentified Ca2+ channels. Additionally, 5-100 μM of m-3M3FBS killed cells in a concentration-dependent manner in OC2 cells. The cytotoxic effect of m-3M3FBS was not reversed by prechelating cytosolic Ca2+ with 1,2-bis(2-aminophenoxy)ethane- N,N,N',N'-tetraacetic acid (BAPTA). Propidium iodide staining data suggest that m-3M3FBS (20 or 50 μM) induced apoptosis in a Ca2+-independent manner.
We were also interested in knowing whether BAPTA suppressed cell death during oxidative stress in MDCK cells. BAPTA loading altered tBHP (tert-butyl hydroperoxide) and H2O2-induced cell death in a concentration-dependent manner. This suggests that the cell death induced by tBHP and H2O2 appears to be Ca2+-dependent in MDCK cells. The tBHP and H2O2-induced cell death was not suppressed by 2 μM U73122 (PLC inhibitor), 50 μM zVAD-fmk (caspase inhibitor), 2 μM cyclosporin A (a potent inhibitor of the MPTP), 20 μM PD98059 (ERK inhibitor) or 2 μM SP600125 (JNK inhibitor). This suggests that the tBHP and H2O2-induced MDCK cells death was not via the PLC, MPTP, caspase, ERK or JNK pathways. Propidium iodide staining, caspase-3 activity assay and cell morphology data suggest that tBHP and H2O2-induced cell death was necrosis, not via apoptosis, and the cell death appears to be caspase-independent and Ca2+-dependent.
The effect of the antidepressant paroxetine on [Ca2+]i in OC2 human oral cancer cells is unclear. This study also explored whether paroxetine changed basal [Ca2+]i levels in suspended OC2 cells by using fura-2 as a Ca2+-sensitive fluorescent dye. Paroxetine at concentrations between 100-1000 μM increased [Ca2+]i in a concentration-dependent manner. The Ca2+ signal was reduced by 50% by removing extracellular Ca2+. Paroxetine-induced Ca2+ influx was inhibited by the store-operated Ca2+ channel blockers nifedipine, econazole and SK&F96365, the phospholipase A2 inhibitor aristolochic acid, and protein kinase C modulators. In Ca2+-free medium, pretreatment with the endoplasmic reticulum Ca2+ pump inhibitor thapsigargin abolished paroxetine–induced [Ca2+]i rise. Inhibition of PLC with U73122 did not alter paroxetine-induced [Ca2+]i rise. Paroxetine at 10-50 μM induced cell death in a concentration-dependent manner. The death was not reversed when cytosolic Ca2+ was chelated with BAPTA. Propidium iodide staining suggests that apoptosis played a role in the death. Collectively, in OC2 cells, paroxetine induced [Ca2+]i rise by causing PLC-independent Ca2+ release from the endoplasmic reticulum and Ca2+ influx via store-operated Ca2+ channels in a manner regulated by protein kinase C and phospholipase A2. Paroxetine also induced cell death in a Ca2+-independent manner.

學位論文審定書………………………..……………… i
誌謝…………………………………………………...... ii
中文摘要……………………………………………….. iii
Abstract………………………………………………… v
Contents…………………………………………........ viii
List of figures…………………………………………… x
List of abbreviations…………………………………… xii
Chapter 1: Introduction………………………………… 1
Apoptosis…………………………………………… 1
Calcium homeostasis…………………………….. 6
Mitogen-activated protein kinases (MAPKs).…… 9
m-3M3FBS………………………………………..... 13
Reactive oxygen species (ROS)………………… 16
Paroxetine………………………………………… ..20
Specific aims...…………………………………….. 22
Chapter 2: Effect of m-3M3FBS on Ca2+ movement in MDCK and OC2 cells.……………………………….. 25
2.1 Introduction…………………………………… 25
2.2 Materials and methods…………………....... 27
2.3 Results………………………………………… 32
2.4 Discussion…………………………………….. 43
Chapter 3: Paroxetine-induced Ca2+ Movement and Death in OC2 Human Oral Cancer Cells………….. 54
3.1 Introduction…………………………………… 54
3.2 Materials and methods…………………….. 56
3.3 Results………………………………………… 60
3.4 Discussion………………………………….. 63
Chapter 4: Conclusions……………………............ 68
References…………………………………………… 72
Figures……………………………………………… 84
Publications and Presentations……………........ 116
Appendix 1: Effect of m-3M3FBS on Ca2+ movement in Madin-Darby canine renal tubular cells. Hum Exp Toxicol 2009; 28: 655-663. …..…………… 118
Appendix 2: Paroxetine-induced Ca2+ Movement and Death in OC2 Human Oral Cancer Cells. Chin J Physiol 2011; 54. In press.………………….......... 127

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