多型性神經膠母細胞瘤(glioblastoma multiforme, GBM)為常見於腦部的惡性癌化腫瘤。經統計顯示，以目前傳統侵入式外科手術切除及放射線治療並搭配化療藥物共同治療，其治療預後五年存活率低於百分之三十，其中藥物耐受性在患者存活率上扮演重要原因。在本研究第一部份之結果發現，從海洋弧菌萃取出的靈菌紅素(prodigiosin)以微莫耳濃度即能毒殺多型性神經膠母細胞瘤細胞株，並且比化療藥物帝盟多(temozolomide)低兩百倍以下，就可抑制癌細胞次球體之產生(cancer cell sphere formation)。靈菌紅素會增加內質網壓力及強烈的自噬作用並引起細胞凋亡相關分子表現，進而導致自噬性死亡(autophagic cell death)。靈菌紅素也會降低於神經膠母細胞瘤細胞中異常上升的AKT分子路徑。此外，也造成代謝酶穀胱甘肽S-轉移酶M3的RNA表現量下降。在本論文第二部份，連續60天帝盟多篩選後的GBM8401神經膠母細胞瘤細胞群中，原生性表現之穀胱甘肽S-轉移酶家族蛋白之蛋白表現有增量的現象。另外，在具有高度抗帝盟多毒殺並高度表現穀胱甘肽S-轉移酶M3之T98G神經膠母細胞瘤細胞，減弱其穀胱甘肽S-轉移酶M3表現，能增強帝盟多毒殺現象，並且降低細胞侵入之能力，並在海馬生物能量測定儀(Seahorse XF Analyzer)的分析結果發現，缺少穀胱甘肽S-轉移酶M3會降低糖解作用。綜合以上結果，穀胱甘肽S-轉移酶M家族蛋白可能在神經膠母細胞瘤中影響化療藥物帝盟多抗性。期望本研究結果能提供具抗化療藥物耐受性之多型性神經膠母細胞瘤之可能治療方向。

Glioblastoma multiforme (GBM) is a frequently malignant primary brain tumor. Even with aggressive treatment strategies, including surgery, radiotherapy, and chemotherapies, the median survival is less than 30% in 5 years. In chemotherapeutic failure, drug resistance is a critical factor affecting the survival rate of patients with cancer. In part I of this thesis, we observed that marine Vibrio bacteria-derived prodigiosin significantly downregulated the growth in micromolar concentrations and inhibited cancer cell sphere formation at concentrations 200 times less than that of chemotherapy-drug temozolomide (TMZ) in GBM cell lines. Moreover, prodigiosin causes endoplasmic reticulum stress with extreme autophagy and induces apoptosis marker expression, which causes autophagic cell death. Prodigiosin attenuates most GBM abnormal increased AKT signaling. Furthermore, prodigiosin decreased glutathione S-transferases mu 3 (GSTM3) mRNA expression. In part II of this thesis, our results showed that subjecting TMZ-resistant GBM8401 glioblastoma cells to continuous TMZ treatment for 60 days resulted in enhanced endogenous GST protein expression. Moreover, the T98G glioblastoma cell line, a pre-existing and highly TMZ-resistant strain with high GSTM3 expression, exhibited increased TMZ toxicity and decreased invasion ability after transfection of GSTM3 gene silencing by siRNA. We also observed downregulated glycolysis ability in GSTM3-downregulated T98G cells using a Seahorse XF Analyzer. These results clarify that the GSTM subfamily might affect chemotherapy drug TMZ resistance in GBM. We expect our results to provide probable solutions for GBM's chemotherapeutic resistance.

論文審定書 i
論文公開授權書 ii
誌謝 iii
中文摘要 iv
Abstract v
Table of contents vi
List of figures xi
List of tables xv
List of abbreviation xvi
General introduction 1
Brain cancer 1
The current therapy of GBM patients 1
The genomic alterations of clinical GBM subtypes 3
Possible treatment strategies for chemotherapeutic resistance in GBM 4
Marine natural products in drug development 5
Concept of this thesis 6
General materials and methods 10
Reagents 10
Cell culture 10
3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay for cell viability analysis 11
RNA isolation and cDNA synthesis 11
Western blotting 11
Acridine Orange staining 12
Statistical analyses 12
Part I. Prodigiosin stimulates endoplasmic reticulum stress and induces autophagic cell death in glioblastoma cells 13
Introduction 14
Background of marine vibrio derived-prodigiosin 14
Endoplasmic reticulum stress and autophagy 14
Autophagy-related programmed cell death: autophagic cell death 15
Cell proliferation and survival-related PI3K/AKT/mTOR pathway in glioblastoma cells 16
The rationale of this research 17
Materials and methods 19
Reagents 19
Antibodies 19
Compound 19
Neurosphere formation 20
Flow cytometry analysis of cell cycle 20
Apoptosis detection using caspase-3 activity assay 21
Semi-quantitative real-time PCR 21
Light chain 3 puncta observation using fluorescence microscopy 22
Observation of prodigiosin localization to the ER using confocal microscopy 23
Results 24
Prodigiosin is a fluorescent chemical compound 24
Prodigiosin induces cell death and morphological changes in human glioblastoma cells 24
Prodigiosin reduces the growth of spheres formed from glioblastoma cells 25
Prodigiosin induces apoptosis in glioblastoma cells 25
Prodigiosin is strongly correlated with calnexin, an ER marker, and induces ER stress and autophagy in glioblastoma cells 26
Prodigiosin suppresses AKT/mTOR signaling and affects autophagic cell death-related protein in glioblastoma cell lines 27
Effect of autophagy inhibitors on prodigiosin-induced autophagic cell death 28
Prodigiosin inhibits GSTM3 mRNA expression in glioblastoma cell lines 28
Conclusion 29
Discussion 30
Figures 36
Part II. The role of GSTM subfamily in chemotherapeutic drug Temozolomide resistance glioblastoma 58
Introduction 59
Chemotherapeutic resistance in GBM treatment 59
Classification and function of metabolic isozyme glutathione s-transferase 60
GST superfamily members in cancer research 62
The role of glutathione s-transferase M3 in brain diseases and its possible functions 63
The role of glycolysis in chemotherapy resistance in cancer therapy 65
GST superfamily members affect invasion in cancer cells 66
Concept of this thesis 67
Methods 68
Antibodies 68
Generation of artificial TMZ resistance glioblastoma cell lines 68
Generation of gene knockdown glioblastoma T98G cells 68
GST activity assay 69
RNA profile transcriptome by Next-generation sequencing 69
Relative quantification of target gene expression by RT-PCR 69
Co-immunoprecipitation assay 70
Transwell chamber invasion assay 70
Results 71
Generation of TMZ-resistant glioblastoma cell lines 71
TMZ resistance level and prognostic markers expression in glioblastoma cell lines 72
Glycolysis stress response of glioblastoma cell lines 72
Examination of GST activity and GST subfamily proteins expression in glioblastoma cell lines 73
GSTM3 may affect TMZ toxicity in T98G glioblastoma cells 74
GSTM3 might be associated with glycolysis in T98G glioblastoma cells 74
GSTM3 affects invasion in T98G glioblastoma cells 75
The most affected genes in GSTM3 knockdown T98G by NGS 76
Conclusion 76
Discussion 78
Figures 83
References 104
Resume 137

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