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系統識別號 U0026-1806201309510900
論文名稱(中文) 探討新穎抗惡性神經膠質瘤藥物”米諾環素”之作用機轉
論文名稱(英文) Studies on the mechanisms of action of minocycline as a novel anti-glioma drug
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 101
學期 2
出版年 102
研究生(中文) 劉威廷
研究生(英文) Wei-Ting Liu
學號 S58941230
學位類別 博士
語文別 英文
論文頁數 116頁
口試委員 指導教授-簡伯武
召集委員-賴明德
口試委員-曾淑芬
口試委員-張文昌
口試委員-陳青周
中文關鍵字 惡性神經膠質瘤  米諾環素  細胞自噬  細胞凋亡  內質網壓力 
英文關鍵字 malignant gliomas  minocycline  autophagy  apoptosis  ER stress 
學科別分類
中文摘要 惡性神經膠質瘤一直是最惡性的癌症之一,儘管神經外科手術、化療和放射治療有所進步,但惡性神經膠質瘤病人的預後仍然非常差。因此,研發針對惡性神經膠質瘤之新療法是急迫且必須的。米諾環素(minocycline, Mino)是第二代的四環黴素衍生物,被認為對許多神經性疾病具有神經保護作用,除此之外,米諾環素也被證明具有抑制血管新生的能力,可以抑制腫瘤細胞的生長。因此本研究在探討米諾環素是否具有治療惡性神經膠質瘤之能力,並探討其中相關的機制。
本論文分為兩個部分,第一部分首先探討米諾環素是否具有抑制惡性神經膠質瘤的能力。細胞存活分析顯示米諾環素具有毒殺惡性神經膠質瘤的能力,免疫螢光染色指出米諾環素並不會引起細胞凋亡或是細胞壞死,反而增加了許多自噬小體,顯示米諾環素可能是透過引起細胞自噬(autophagy)而造成惡性神經膠質瘤死亡,細胞自噬被認為是第二型程序性細胞死亡(programmed cell death type II)。此外,透過西方點墨法,發現投予米諾環素會抑制AKT/mTOR訊息傳遞路徑的活性,但會活化ERK1/2訊息傳遞路徑的活性;而在惡性神經膠質瘤的腫瘤異體移植動物模式中,米諾環素可以有效抑制腫瘤的生長。這些結果顯示:米諾環素可以透過引起自噬作用毒殺惡性神經膠質瘤,因此,在治療惡性神經膠質瘤中,米諾環素是非常具有發展潛力的。然而,我們發現當細胞自噬被抑制,米諾環素仍可透過引起細胞自我凋亡,顯示米諾環素有其他機轉可以引起細胞自噬及細胞凋亡的轉換。第二部分,我們探討米諾環素是否藉由內質網壓力引起細胞自噬及細胞凋亡,並釐清細胞自噬及細胞凋亡的關係。內質網(endoplasmic reticulum, ER)對於調控細胞恆定是非常重要的胞器,在癌細胞中也扮演非常重要的角色。我們發現米諾環素會在短時間內活化內質網壓力感應分子(PERK),接著活化下游分子eIF2α及增加CHOP(內質網壓力標記)的大量表現,顯示米諾環素在誘發細胞自噬前會先活化內質網壓力。我們也發現內質網壓力調控因子(GRP78)會在神經膠質瘤細胞中大量表現,米諾環素處理後會增加GRP78的表現量但會干擾GRP78與PERK的結合,顯示米諾環素是藉由影響GRP78與PERK的結合引起內質網壓力。此外,抑制內質網壓力也會降低米諾環素對惡性神經膠質瘤的毒殺性;當細胞自噬被抑制時,米諾環素仍可活化內質網壓力並透過細胞凋亡引起惡性神經膠質瘤死亡,而細胞自噬抑制劑抑制自噬作用之下並不影響米諾環素抑制AKT/mTOR的活性,顯示米諾環素主要透過內質網壓力引起自噬作用死亡。而當自噬作用被抑制時,米諾環素會透過抑制AKT/mTOR活性而引起細胞凋亡。在原位神經膠質瘤動物模式中,生物冷光影像結果顯示米諾環素可抑制惡性神經膠質瘤生長,且可延長實驗動物的存活時間。然而,當內質網壓力被抑制時,則會降低米諾環素在動物體內的抗腫瘤能力。綜合以上結果得知,米諾環素會透過內質網壓力誘發自噬作用和自我凋亡。
米諾環素具有優越的通過血腦障壁之能力,且不會傷害正常的神經和神經膠細胞,這對於治療惡性膠質瘤是很有幫助的且非常重要的。本論文發現米諾環素能有效抑制惡性神經膠質瘤的生長,而內質網壓力與細胞自噬在其中扮演重要角色;並進一步了解內質網壓力、細胞自噬與細胞凋亡的關係。這些結果結合臨床可用性及安全性,指出米諾環素對於惡性神經膠質瘤的治療是非常具有潛力的。
英文摘要 Malignant gliomas are among the most devastating cancers. Despite advances in the diagnosis and treatment, the prognosis of patients with malignant gliomas remains very poor. Therefore, exploration of a new approach is timely needed. Minocycline (Mino), a second-generation tetracycline, has marked neuroprotective properties in various models of neurological diseases. Besides its neuroprotection, it has also been demonstrated that Mino has antiangiogenic properties to inhibit tumor growth. This study aims to investigate whether Mino can be used as a potential anticancer agent for malignant glioma and to study the underlying mechanisms of Mino.
Two parts are included in my thesis. (1) To investigate whether Mino has the probability of tumor suppression. Cell viability assay showed that Mino induced cell death in malignant glioma cells. Immunostaining indicated that Mino treatment did not induce apoptosis or necrosis, whereas increased autophagic vacuoles in the cytoplasm revealed that the glioma cell death was mediated by autophagy activation in response to Mino treatment. Autophagy has been identified as programmed cell death type II. Besides, AKT/mTOR pathway was suppressed and ERK1/2 pathway was activated in glioma cells upon treatment with Mino. Moreover, Mino effectively inhibited tumor growth in the xenograft tumor model of glioma cells. These results suggest that Mino may kill glioma cells by inducing autophagic cell death. Thus, Mino is a promising agent in the treatment of malignant gliomas. However, when autophagy was inhibited, Mino still induced cell death through the activation of apoptosis. It suggests that unknown mechanisms are involved in the autophagy-apoptosis switch which is induced by Mino. (2) To investigate whether Mino induces autophagy and apoptosis through ER stress and clarify the relationships between autophagy and apoptosis. Endoplasmic reticulum (ER) has emerged as a major site of cellular homeostatic regulation in cancer. We found that Mino activated PERK, an ER stress sensor, in a short time and subsequently increased eIF2α phosphorylation and the expression of CHOP, which are markers of ER stress. It suggested that Mino induced ER stress in prior to activation of autophagy. We also found that ER stress regulator, GRP78 was upregulated in glioma. Mino treatment increased GRP78 expression and reduced the binding of GRP78 with PERK, leading to ER stress. Besides, inhibition of ER stress attenuated the Mino-induced glioma cell death. When autophagy was inhibited, Mino still activated ER stress and induced apoptosis in glioma cells. However, autophagy but not Mino-suppressed AKT/mTOR pathway was attenuated by autophagy inhibitor. These results suggest that Mino induces autophagic cell death primarily by eliciting ER stress response. Autophagy inhibition switches cell death to apoptosis due to the suppression of AKT/mTOR cascades by Mino. In the orthotopic glioma model, bioluminescent imaging showed that Mino inhibited the growth of glioma and prolonged the survival of mice. Inhibition of ER stress but not autophagy attenuated Mino-induced anti-proliferation in vivo. Taken together, these results suggest that Mino triggers apoptosis and autophagic cell death by inducing ER stress.
Minocycline has superior penetration across the blood-brain barrier to facilitate the effect of treatment and does not cause damage on normal neuron or glia cells. Coupled to clinical availability and safe track record, this thesis strongly suggested that minocycline is a potential therapeutic agent for malignant glioma.
論文目次 中文摘要………………………………………………………………………………………………………………………………………01
Abstract in Chinese
英文摘要………………………………………………………………………………………………………………………………………04
Abstract in English
致謝………………………………………………………………………………………………………………………………………………08
Acknowledgement
縮寫檢索表…………………………………………………………………………………………………………………………………09
Abbreviations
Chapter 1: Introduction……………………………………………………………………………………………10
1.1 Brain tumor and glioblastoma……………………………………………………11
1.2 Minocycline…………………………………………………………………………………………………12
1.3 Autophagy………………………………………………………………………………………………………14
1.4 Endoplasmic reticulum stress response (ESR) …………17
1.5 Objectives of the study…………………………………………………………………22
Chapter 2: Materials and Methods……………………………………………………………………25
Chapter 3: Minocycline inhibits the growth of glioma by inducing autophagy.………………………………………………………………………………………………………34
3.1 Introduction………………………………………………………………………………………………35
3.2 Results……………………………………………………………………………………………………………38
3.3 Discussion……………………………………………………………………………………………………43
Chapter 4: Minocycline inhibits the growth of glioma through endoplasmic reticulum stress-induced apoptosis and autophagic cell death…………………………………………………………………………………………………55
4.1 Introduction……………………………………………………………………………………………56
4.2 Results…………………………………………………………………………………………………………58
4.3 Discussion…………………………………………………………………………………………………67
Chapter 5: Conclusions and prospect……………………………………………………………87
References………………………………………………………………………………………………………………………………93
Appendix…………………………………………………………………………………………………………………………………110
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