光動力療法所引起的細胞死亡與Procaspase-3的後轉譯修飾作用

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研究生：	謝雅如 Hsieh, Ya-Ju
論文名稱：	光動力療法所引起的細胞死亡與Procaspase-3的後轉譯修飾作用 Cell death and post-translational modification of procaspase-3 induced by Photofrin-mediated Photodynamic treatment in mammalian cells
指導教授：	呂平江 Lyu, Ping-Chiang
口試委員:
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 生物資訊與結構生物研究所 Institute of Bioinformatics and Structural Biology
論文出版年：	2010
畢業學年度：	99
語文別：	英文
論文頁數：	214
中文關鍵詞：	光照療法、內質網、內質網鈣離子通道、細胞死亡、含氧活化分子
外文關鍵詞：	Photodynamic therapy, endoplasmic reticulum, SERCA, caspase-3, cell death, reactive oxygen species
相關次數：	點閱：2 下載：0
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Photofrin® is the first generation photosensitizer for photodynamic treatment (PDT) of cancer, and Photofrin-PDT-triggered cell death represents its major therapeutic effect. Although diverse cell death phenotypes induced by Photofrin-PDT have been observed for some time, the mechanism(s) underlying this diversity remain elusive. Using human epidermoid carcinoma A431 cells as a model, we previously showed that distinct cell death types could be triggered which depend on Photofrin location and PDT dosage [Hsieh et al., (2003) J. Cell. Physiol. 194, 363-375]. In this thesis, the effects of Photofrin-PDT on A431 cells with intracellular organelle-localized Photofrin were further investigated. My study showed that PDT of A431 cells with intracellular organelle-localized Photofrin caused dilation of endoplasmic reticulum (ER), which results in the perinuclear vacuole formation. These dilated vacuoles are just proximal to the intracellular DCFDA-sensitive reactive oxygen species (ROS) elicited post Photofrin-PDT. The PDT-induced alteration of ER structure is similar to that triggered by thapsigargin, a ER Ca2+-ATPase inhibitor that perturb Ca2+ homeostasis, suggesting a role of Ca2+ in the formation of PVs. These results unravel a novel cell response to ER stress elicited by PDT when intracellular organelles are selectively loaded with Photofrin. To explore the control mechanism(s) of multiple cell death phenotypes caused by PDT treatment, the possible modification/regulation of caspase-3, a critical executioner of apoptosis, by Photofrin-PDT was further investigated. The results revealed for the first time that Photofrin-PDT can modify and inactivate procaspase-3, some of which turned into novel species with extraordinary high molecular weight (HMW) (~90 kDa) observed in SDS-PAGE. Photofrin-PDT generated ROS and blocked the activation of procaspase-3 by the upstream protease, caspase-8. Mass spectrometry-based analysis of post-translational modification of procaspase-3 using FT-MS and 16O/18O- and 14N/15N-labeling quantitative methods showed that Photofrin-PDT caused Met oxidation of procaspase-3 in this process mainly on Met-27, 39 and 44 in a Photofrin dose-dependent manner, but the active site Cys163 remained largely unmodified. Site direct mutagenesis (Met to Leu) experiments further denoted Met-44 as a critical residue for regulating procaspase-3 activation. In addition, the caspase-3-containing HMW products could be induced in various human cell lines in an oxidative stress-dependent manner, as well as in a mouse xenograft tumor model. Experiments using ectopically expressed procaspase-3 tagged with different tags indicated that the HMW products were resulted from cross-linking of procaspase-3 itself. In conclusion, this thesis have characterized different types of cell death elicited by Photofrin-PDT, in which Met oxidation and HMW product formation of procaspase-3 may play important roles in regulating caspase-3 activity and hence the cell fate determination.

Photofrin 是光動力療法中用來治療癌症的第一代光敏劑，主要的治療效果可導致癌細胞的死亡。許多研究發現PDT可以導致各種不同型態的細胞死亡，但是其中的機制還不是非常清楚。我們利用A431細胞進行PDT的研究，發現Photofrin不同處理時間，會分布在細胞不同的區域，照光處理後可以造成細胞不同的死亡型態 [Hsieh et al., (2003) J. Cell. Physiol. 194, 363-375]。在本研究中發現，當Photofrin分布在細胞內胞器中時，處理光照後2-8小時會導致細胞核周圍的空泡形成，我們證明空泡時由ER形成的，並且和ROS的形成是相關的；利用一個ER膜上的Ca2+-ATPase (SERCA) 的抑制劑處理，也可以看到相同的空泡的形成。本研究發現了一個新的細胞反應，PDT處理後會造成ER的壓力並導致空泡的形成。此外，caspase-3在細包凋亡中扮演一個執行者的角色，我們證實了PDT處理後會導致procaspase-3被修飾並且失去活性，一部分的procaspase-3還會形成三倍的高分子量產物。高劑量的PDT處理可以阻止內生性的以及重組的procaspase-3被上游的蛋白質(caspase-3)活化。利用FT-MS分析蛋白質量差異，或用16O/18O以及 15N穩定同位素標定的定量實驗中，我們發現氧化是PDT所造成的主要修飾作用。定量結果顯示，Met-27, -39 及 -44是氧化最明顯的胺基酸，而活性中心Cys163沒有明顯的變化。在procaspase-3-D3A中點突變的實驗結果顯示，M44L的突變株活性相較於其他突變株低 (M27L, M39L and M222L)；在野生型中點突變的實驗結果顯示，M44L的突變株被上游caspase-8活化的情況較差；綜合以上的結果顯示高劑量PDT處理後造成Methionine氧化以致procaspase-3不易被活化，這或許可以解釋PDT造成的複雜的細胞死亡；更進一步的，我們認為高分子產物的行程也可能在細胞死亡中扮演一個角色。我們發現高分子量產物會在各種細胞形成，並且與氧化壓力相關，而高分子量的形成也可以在動物實驗中看到。高分子量產物是經由修飾已生成的蛋白質所形成，並造成原來的procaspase-3的減少，在細胞中表現myc- 以及EGFP-procaspase-3 經PDT處理後更證明了高分子量產物是procaspase-3之間彼此共價鍵結形成。但高分子量產物的鍵結不是非常穩定，在純化的過程中會再度斷裂變回單體結構，目前我們正在尋找純化的方法以及鑑定共價鍵結的位置。綜合上述結論，在PDT處理後，我們鑑定不同的細胞死亡型態；另一方面，PDT處理後造成caspase-3氧化，形成高分子量產物，並失去活性，這些caspase-3的改變可能調控了細胞死亡的路徑。

Chapter I. Introduction
1.1    PDT induced cell death and its clinical applications………………………………...…………1
1.2    PDT effect of photosensitizer’s different locations in our previous study………...……...……3
1.3    Caspase-3 ………...……………………………………………………...…………………..…4
1.4    High molecular weight products………...………………………………………………...……5
1.5    Proteomic analysis………...……………………………………………………………………7
1.6    Specific aims ………...…………………………………………………………………………8
Chapter II. Materials and methods
2.1    Materials………...……………………………………………………………………………9
2.2    Plasmid Construction………………………………………………………………………...9
2.3    Cell culture……………………………………………………………..………………...…10
2.4    Transfection……………………………………………………………..………………..…11
2.5    PDT treatment………………………………………………………………………………11
2.6    Collection of proteins secreted by A431 cells………………………………………………12
2.7    Immunoprecipitation………………………………………………………………….……12
2.8    Immunoblot ……………………………………………………………..…………………12
2.9    Cell viability assay……………………………………………………………….….. ……12
2.10    Detection of apoptosis…………………………………………………………….......……13
2.11    Detection of intracellular ROS ………………………………………………….…………13
2.12    Immunostaining ……………………………………………………………..……….….…13
2.13    Selection of A431 cell lines stably expressing organelle trackers ………………..…..……14
2.14    Live-cell imaging ………………………………………………………………..…………14
2.15    Nude mice tumor model ……………………………………………………………....……14
2.16    Purification of Recombinant Caspase-3……………………………………………...…..…15
2.17    HMW Protein purification …………………………………………………..…………..…15
2.18    Caspase-3 Activity Assay ………………………………………………………………..…15
2.19    Measurement of Intact Protein Molecular Weight by FT-ICR MS …………………...……16
2.20    Post-digestion 18O Labeling and quantitation
2.20.1    Post-digestion 18O Labeling………………….……………………………………16
2.20.2    LC-MS/MS………………….……………………………………….……………17
2.20.3    MS Data Search………………….……………………………………..…………18
2.20.4    Quantitation Pipeline for Peptide Identification and Modification……………….18
2.21    15N Labeling and Quantitation …………………………………………………………..…20
2.22    MALDI-TOF mass spectrometric analysis of SDS-gel-fractionated proteins …………..…22
Chapter III. Results
Part I: Characterization of photodynamic therapy responses elicited in A431 cells containing intracellular organelle-localized Photofrin
1.    Phenotypic characteristics of A431 cells following exposure to different Photofrin-PDT regimens…………………………………………………………………...………………..…23
2.    Type II PDT treatment reduces viability and impairs protein secretion by A431 cells…….…24
3.    Localization of intracellular ROS formed in live cells after PDT…...……………………..…25
4.    Characterization of PVs…………………………………………………………..…………...27
5.    Perturbation of microtubule dynamics has little effect on PV formation in PDT-treated cells……………………………………………………………………………………………28
6.    Thapsigargin, a selective inhibitor of sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA), also induces PV formation in A431 cells……………………………………….…29
Part II: Photofrin-mediated photodynamic treatment causes methionine oxidation of procaspase-3 and impairs its activation by upstream caspase
1.    Photofrin-PDT elicits a bell-shape, dose-dependent activation of caspase-3 activity in human cancer cell lines……………………………………………………………………………….30
2.    Photofrin-PDT inhibits caspase-8-mediated cleavage/activation of caspase-3 in A431 cell lysates……………………………………………………………………………...………….32
3.    Photofrin-PDT directly elicits chemical modification on procaspase-3 protein and concomitantly impairs its enzyme activity ………………………………………………..….33
4.    Accurate mass measurement of procaspase-3-D3A treated with or without Photofrin-PDT by FT-ICR MS ………………………………………………………………….………….…….35
5.    Analysis of Photofrin-PDT-elicited modification of procaspase-3-D3A using 16O/18O-labeling quantitative proteomics strategy ……………………………………………….………….….36
6.    Confirmation of Photofrin-PDT-elicited Met oxidation of procaspase-3-D3A using 15N -labeling quantitative proteomics strategy ……………………………………….…………...39
7.    Substitution of Met-44 by Leu significantly attenuates the proteolytic maturation of caspase-3………………………………………………………………………………………41
Part III: Characterization of the HMW products derived from the Photofrin-PDT-modified caspase-3
1.    Photofrin-PDT induces covalent modification of caspase-3 in various human cell lines………………………………………………………………………………………..…..43
2.    Cellular characteristics of the Photofrin-PDT-induced modification of procaspase-3………..44
3.    Cross-linking of procaspase-3 itself is responsible for the formation of caspase-3-containing HMW species in Photofrin-PDT-treated cells………………………………………………...45

Chapter IV. Discussion...................................................................................................................49
Chapter V. Limitations and significance of this study, and prospective..62       References......................................................................................................................................64
Figures
Fig. 1.Distinct cell death types and morphological changes induced in A431 cells by different Photofrin-PDT regimens…………….…………………………………………………….……76
Fig. 2. Effects of type II PDT treatment on the viability, MAPK activity, and protein secretion of A431 cells..…………………………………………………………………………………..…….…..78
Fig. 3. ROS formation around PVs in A431 cells after type II PDT treatment…………………….…..80
Fig. 4. Effects of ROS scavengers on the PV formation in A431 cells treated with the type II PDT protocol. ………………………………………………………………………….………….….82
Fig. 5. Identification of the origin of PVs formed in PDT-treated cells using organelle trackers……...83
Fig. 6. Time lapse observations of the vesicle formation in A431 cells treated with type II PDT….….85
Fig. 7. Time-lapse observations of PV formation in PDT-treated A431 cells stably overexpressing the EYFP-ER tracker…………………………………………………………………………….….86
Fig. 8. Effects of nocodazole and Taxol on PDT-triggered ER vacuolization in A431 cells………..….87
Fig. 9. Thapsigargin induces PV formation in A431 cells……………………….………………….….89
Fig.10.Effects of Photofrin-PDT on the activation and modification of procaspase-3 in A431 and Jurkat T cells………………………………………………………...……………………………….…90
Fig.11.Photofrin-PDT impairs the proteolytical processing/activation of procaspase-3 by the upstream protease, caspase-8………………………………………………………………………………91
Fig.12.Photofrin-PDT causes inactivation and modification of recombinant procaspase-3-D3A…..…92
Fig.13.Intact protein measurement by FT-ICR MS……………………………………………….....…94
Fig.14.The 16O/18O quantitative proteomics strategy for analyzing procaspase-3-D3A post translational modifications. ……………………………………………………………….…………………..97
Fig.15.Sequence coverage of recombinant procaspase-3-D3A after Photofrin-PDT treatment from 16O/18O labeling experiments…………...…………………………………………………….....99
Fig.16.The representative MS and MS/MS spectra of selected peptide pairs used for the quantitation of Met oxidation in procaspase-3-D3A treated with and without PDT……………………….…..100
Fig.17.Methionine oxidation was the most significant modification between control and PDT samples assayed by 15N labeling……………………………………………………………….…….….106
Fig.18.Caspase-3 activity assay of Met27, 39, and 44 mutated to Leu with or without PDT treatment………………………………………………………………………………………..108
Fig.19.M44L delayed caspase-3 maturation process both in recombinant protein autoprocess and upstream caspase-8 digestion……………………………………………………………..……109
Fig.20.The structure of caspase-3……………………………………………………………….....….110
Fig.21.Photofrin-PDT induces modification of caspase-3 in various human cell lines. ……………...111
Fig.22.Cellular characteristics of the Photofrin-PDT-induced modification of procaspase-3 ……..…113
Fig.23 Singlet oxygen scavenger prevented the Photofrin-PDT-triggered formation of the caspase-3- containing HMW species………………………………………………….……………...……114
Fig.24.Cross-linking of procaspase-3 itself is responsible for the formation of caspase-3-containing HMW species in Photofrin-PDT-treated cells………………………………………………….115
Fig. 25. The model of different types of cell death induced by Photofrin-PDT………………………116

Tables
Table 1. List of tryptic peptides of procaspase-3-D3A whose levels show >1.5 fold increase after Photofrin-PDT treatment using the 18O-labeling strategy……………………………….…..117
Table 2. Peptide ratio of PDT/Ctrl labeled by 16O/18O……...…………………………………………118
Table 3. Analysis of the oxidized peptide yields of procaspase-3-D3A treated with different doses of Photofrin-PDT using the 15N-labeling strategy…………….…………..…………………….119
Table 4. Precursor peptide lost after different dose PDT treatment using 15N stable isotope  labeling……………………………………………….………………………………...……120
Appendix Figures
Appendix Fig. 1. Type of cancer and approved drugs (2003)…………………………………………121
Appendix Fig. 2. Appendix Fig. 2. Mechanism of action of photodynamic therapy (PDT). ………...122
Appendix Fig. 3. Structure of photosensitizers………………………………………………………..123
Appendix Fig. 4. Type I and type II reaction in photodynamic therapy (PDT)……………………….124
Appendix Fig. 5. Photodynamic therapy induces activation of antigen-specific T cells……………...125
Appendix Fig. 6. Apoptosis and Necrosis phenotypes………………………………………………...126
Appendix Fig. 7. Distinct death phenotypes of A431 cells triggered by photodynamic therapy (PDT) with differentially localized Photofrin. ……………………………………...…….127
Appendix Fig. 8. Subcellular distribution of Photofrin1 in A431 cells. ……………………….……..128
Appendix Fig. 9. Morphological change of A431 cells triggered by PDT at various Photofrin1 concentrations and different time intervals. ……………………………………….129
Appendix Fig. 10. Photofrin1-PDT immediately elicits intracellular reactive oxygen species (ROS) formation and enlarges the size of A431 cells……………………………………..130
Appendix Fig. 11. Apoptosis: the ‘extrinsic’ and ‘intrinsic’ pathways to caspase activation…………132
Appendix Fig. 12. Domain organization of human caspases………………………………………….133
Appendix Fig. 13. Cartoon representation of the two molecular mechanisms of pro-caspase activation…………………………………………………………………………...134
Appendix Fig. 14. ER stucture maintenance..........................................................................................135
Appendix Fig. 15. SERCA pump and calcium alteration in cell death regulation……………………136
Appendix Fig. 16. Recombinant procaspase-3-D3A scheme and expression pattern………………...137
Appendix Fig. 17. The MS/MS spectra of post-translational modification peptides identified by error tolerant search………………………………………………………………...……138
Appendix Fig. 18. Mass spectrometric analysis of the caspase-3-containing HMW species immunoprecipitated from A431 cells. ……………………………….…………….211
Appendix Fig. 19. Different organelle-localized photosensitizer (PS)-PDT induces distinct signaling pathways. ………………………….……………………………………………….213

Appendix Table :
Tryptic peptide mass fingerprints of protein bands from the caspase-3 immunocomplexes……….....214

                                

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