探討resveratrol和osajin對鼻咽癌之抗腫瘤作用及機制

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黃宗騰(Tsung-Teng Huang) 查詢紙本館藏

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論文名稱

探討resveratrol和osajin對鼻咽癌之抗腫瘤作用及機制
(The anti-tumor effects and mechanisms of resveratrol andosajin in human nasopharyngeal carcinoma)

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摘要(中)

白藜蘆醇 (resveratrol) 為一天然多酚類化合物。先前研究指出白藜蘆醇具有誘導癌症細胞走向細胞凋亡之抗腫瘤的特性。然而尚未有研究指出白藜蘆醇對人類鼻咽癌細胞是否具相同之抗腫瘤特性，所以本研究則探討白藜蘆醇對人類鼻咽癌細胞之抗腫瘤作用及機制。實驗結果顯示，白藜蘆醇能有效的抑制人類鼻咽癌細胞的細胞存活率，且此細胞存活率的降低是由於細胞凋亡所引起。進一步探討白藜蘆醇造成鼻咽癌細胞凋亡的分子機制，發現白藜蘆醇會導致粒線體膜電位的破壞、細胞色素c (cytochrome c) 的釋放、Fas配位體 (FasL) 的增強表現及抑制葡萄糖調節蛋白78kDa (GRP78)的表現，並且伴隨著硫胱氨酸蛋白酶 (caspases) -3、-4、-8和 -9的活化，最後導致DNA的片段化及細胞死亡。除此之外，白藜蘆醇也能增強促細胞凋亡蛋白 (Bax) 的表現及抑制抗細胞凋亡蛋白 (Bcl-2) 的表現。因此，白藜蘆醇能透過粒線體、死亡受體及內質網受迫力 (ER stress) 等調控路徑誘導人類鼻咽癌細胞走向細胞凋亡。白藜蘆醇可作為鼻咽癌治療之有效化合物。
Osajin為一黃酮類化合物。先前研究同樣發現osajin具有抗腫瘤的特性，然而osajin造成腫瘤細胞死亡的機制尚未完全清楚。本研究同樣探討osajin對人類鼻咽癌細胞之抗腫瘤作用及機制。實驗結果顯示，osajin能有效的抑制人類鼻咽癌細胞的細胞存活率，且此細胞存活率的降低是由於細胞凋亡所引起。進一步探討osajin造成鼻咽癌細胞凋亡的分子機制，發現osajin會導致粒線體膜電位的破壞、細胞色素c (cytochrome c) 的釋放、Fas配位體 (FasL) 的增強表現及抑制葡萄糖調節蛋白78kDa (GRP78)的表現，並且伴隨著硫胱氨酸蛋白酶 (caspases) -3、-4、-8和 -9的活化，最後導致DNA的片段化及細胞死亡。除此之外，osajin同樣也能增強促細胞凋亡蛋白 (Bax) 的表現及抑制抗細胞凋亡蛋白 (Bcl-2) 的表現。因此，osajin也能透過粒線體、死亡受體及內質網受迫力 (ER stress) 等調控路徑誘導人類鼻咽癌細胞走向細胞凋亡。Osajin也可作為鼻咽癌治療之有效化合物。

摘要(英)

Resveratrol, a naturally occurring dietary compound with chemopreventive properties has been reported to trigger a variety of cancer cell types to apoptosis. Whether resveratrol shows any activity on human nasopharyngeal carcinoma (NPC) cells remained to be determined. The aim of this study was to investigate the effect and mechanism of resveratrol on human NPC cells. Treatment of resveratrol resulted in significant decrease in cell viability of NPC cell lines in a dose- and time-dependent manner. A dose-dependent apoptotic cell death was also measured by flow cytometery analysis. Molecular mechanistic studies of apoptosis unraveled resveratrol treatment resulted in a significant loss of mitochondrial transmembrane potential, release of cytochrome c, enhanced expression of Fas ligand (FasL), and suppression of glucose-regulated protein 78 kDa (GRP78). These were followed by activation of caspases-3, -4, -8 and -9, subsequently leading to DNA fragmentation and cell apoptosis. Furthermore, up-regulation of proapoptotic Bax and down-regulation of antiapoptotic Bcl-2 protein were also observed. Taken together, resveratrol induces apoptosis in human NPC cells through regulation of multiple apoptotic pathways, including death receptor, mitochondria and endoplasmic reticulum (ER) stress. Resveratrol can be developed as an effective compound for human NPC treatment.
Osajin is a prenylated isoflavone showing antitumor activity in different tumor cell lines. The underlying mechanism of osajin-induced cancer cell death is not clearly understood. In the present study, the mechanisms of osajin-induced cell death of human nasopharyngeal carcinoma (NPC) cells were explored. Osajin was found to significantly induce apoptosis of NPC cells in a dose- and time-dependent manner. Multiple molecular effects were observed during osajin treatment including a significant loss of mitochondrial transmembrane potential, release of cytochrome c into the cytosol, enhanced expression of Fas ligand (FasL), suppression of glucose-regulated protein 78 kDa (GRP78), and activation of caspases-3, -4, -8 and -9. In addition, up-regulation of proapoptotic Bax protein and down-regulation of antiapoptotic Bcl-2 protein were also observed. Taken together, osajin induces apoptosis in human NPC cells through multiple apoptotic pathways, including the extrinsic death receptor pathway, and intrinsic pathways relying on mitochondria and endoplasmic reticulum stress. Thus, osajin could be developed as a new effective and chemopreventive compound for human NPC.

關鍵字(中)

★ 細胞凋亡
★ 鼻咽癌

關鍵字(英)

★ nasopharyngeal carcinoma
★ apoptosis

論文目次

摘要 i
Abstract ii
Acknowledgements iv
Table of contents v
List of figures viii
Abbreviation ix
Chapter 1 Introduction 1
1.1 Nasopharyngeal Carcinoma 1
1.1.1 Aetiology of NPC 1
1.1.2 Histological types of NPC 2
1.1.3 Treatment of NPC 3
1.2 Chemoprevention of cancer 3
1.3 Resveratrol 5
1.3.1 Resveratrol induces death receptor apoptosis
pathway in cancer cells 6
1.3.2 Resveratrol induces mitochondrial apoptosis
pathway in cancer cells 6
1.3.3 Resveratrol-induced apoptosis is mediated via
modulation of Bcl-2 family proteins 7
1.3.4 Resveratrol induces ER stress-mediated apoptosis
pathway in cancer cells 8
1.3.5 Resveratrol induces apoptosis in vivo 9
1.4 Osajin 10
1.5 Apoptosis 11
1.5.1 The extrinsic apoptosis pathway 12
1.5.2 The intrinsic apoptosispathway 13
1.5.3 The Bcl-2 family proteins 13
1.5.4 The ER stress-mediated apoptosis pathway 14
1.6 The objectives of the thesis 16
Chapter 2 Materials and methods 17
2.1 Reagents 17
2.2 Cell lines and cell culture 17
2.3 Cell viability assay 17
2.4 Annexin V-PI binding assay 18
2.5 Detection of DNA fragmentation 18
2.6 Caspase activity assay 19
2.7 Transfection of small interfering RNA (siRNA) 19
2.8 Mitochondria membrane potential detection assay 20
2.9 Western blot analysis 20
2.10 RNA isolation and reverse transcriptase-polymerase
chain reaction (RT-PCR) 21
2.11 Immunoprecipitation 22
2.12 Statistical analysis 22
Chapter 3 Results 23
3.1 Resveratrol induces apoptosis of human nasopharyngeal
carcinoma cells via activation of multiple apoptotic
pathways 23
3.1.1 Resveratrol reduces the viability of human NPC
cells 23
3.1.2 Resveratrol induces apoptosis and DNA
fragmentation in TW04 cells 23
3.1.3 Resveratrol activates caspase-mediated
apoptosis in TW04 cells 24
3.1.4 Resveratrol induces loss of mitochondrial
membrane potential and release of cytochrome c
into cytosol of TW04 cells 25
3.1.5 Resveratrol induces FasL/CD95L expression in
TW04 cells 25
3.1.6 Resveratrol modulates the level of Bcl-2
family proteins in TW04 cells 26
3.1.7 Differential regulation of GRP78/BiP and
CHOP/GADD153 in resveratrol-induced apoptosis
of TW04 cells 26
3.2 Activation of multiple apoptotic pathways in human
nasopharyngeal carcinoma cells by the prenylated
isoflavone, osajin 27
3.2.1 Osajin reduces the viability of human NPC
cells 27
3.2.2 Osajin induces apoptosis and DNA fragmentation
in TW04 cells 27
3.2.3 Osajin induces caspase-mediated apoptosis in
TW04 cells 28
3.2.4 Osajin induces loss of mitochondrial membrane
potential and release of cytochrome c into
cytosol of TW04 cells 29
3.2.5 Osajin induces FasL/CD95L expression in TW04
cells 30
3.2.6 Osajin modulates the level of Bcl-2 family
proteins in TW04 cells 30
3.2.7 Differential regulation of GRP78/BiP and
CHOP/GADD153 in osajin-treated TW04 cells 31
Chapter 4 Discussion 32
References 40
List of figures
Fig. 1. Effect of resveratrol on the viability of human
NPC cells 59
Fig. 2. Resveratrol treatment induces apoptosis and DNA
fragmentation in TW04 cells 60
Fig. 3. Resveratrol induces caspase-dependent apoptosis
in TW04 cells 61
Fig. 4. Resveratrol causes disruption of mitochondrial
membrane potential and release of cytochrome c
into cytosol 62
Fig. 5. Effect of resveratrol on the expression of
Fas/CD95, FasL/CD95L, GRP78/BiP,CHOP/GADD153
and Bcl-2 family proteins in TW04 cells 63
Fig. 6. Schematic model for the mechanisms of
resveratrol-induced apoptosis in human NPC cells 64
Fig. 7. Effect of osajin on the viability of human NPC
cells 65
Fig. 8. Osajin treatment induces apoptosis and DNA
fragmentation in TW04 cells 66
Fig. 9. Osajin induces caspase-dependent apoptosis in
TW04 cells 67
Fig. 10. Osajin causes disruption of mitochondrial
membrane potential and release of cytochrome c
into cytosol 68
Fig. 11. Effect of osajin on the expression of Fas/CD95,
FasL/CD95L, GRP78/BiP,CHOP/GADD153 and Bcl-2
family proteins 69
Fig. 12. DNA fragmentation assay shows inhibition of
apoptosis in osajin-treated NPC cells by
anti-Fas mAb ZB4 70
Fig. 13. Co-immunoprecipitation of Bax and Bcl-2 in
osajin-treated NPC cells 71
Fig. 14. Schematic model for the mechanisms of osajin-
induced apoptosis in human NPC cells 72

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指導教授

劉阜果(Fu-Guo Liu)

審核日期

2011-6-13

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