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Please use this identifier to cite or link to this item: http://ntour.ntou.edu.tw:8080/ir/handle/987654321/34675

Title: Clozapine透過Wnt/β-catenin和p21-dependent途徑抑制大腸直腸癌細胞株生長之探討
Clozapine Inhibits Colorectal Cancer Cell Growth via Wnt/β-catenin and p21-Dependent Pathways
Authors: Shih-Chieh Hsiung
Contributors: NTOU:Institute of Bioscience and Biotechnology
Keywords: 大腸直腸癌
Date: 2013
Issue Date: 2013-10-07T02:45:05Z
Abstract: 臨床統計精神分裂症患者罹患癌症機率相較於正常人低,文獻指出抗精神病藥物會抑制乳癌、肺癌和神經母細胞瘤等細胞株的生長,但詳細分子機制並不清楚。Wnt/β-catenin路徑的不正常活化造成的細胞異常增生,在大腸直腸癌中扮演重要的角色。本研究利用大腸直腸癌細胞株HCT116和SW480探討抗精神病藥物clozapine抑制大腸直腸癌的能力以及對Wnt/β-catenin 路徑的影響。初步結果從MTT assay和clonogenic assay證實抗精神病藥物clozapine以dosage-dependent及time-dependent的方式抑制大腸直腸癌細胞的增生,real-time PCR和西方轉漬結果顯示clozapine抑制β-catenin的mRNA及蛋白量,以及β-catenin下游標的蛋白cyclin D1的表現量。推論抗精神病藥物clozapine可能是透過抑制β-catenin轉錄抑制大腸直腸癌的細胞株生長。 另一方面,根據先前實驗室的結果發現在HCT116 大腸直腸癌細胞株clozapine 會使癌細胞產生reactive oxygen species (ROS)以及使p21的蛋白表現量上升,而根據文獻研究顯示 p21蛋白可保護細胞免於氧化壓力的傷害。本研究將探討 clozapine誘導產生的ROS與p21蛋白之相關性。初步結果MTT assay和clonogenic assay證明抗精神病藥物clozapine會抑制大腸直腸癌細胞的增生是p53-independent途徑,且在相同濃度的clozapine處理,HCT116 p21-/-細胞株被抑制更加顯著。相較於HCT116 p21-/-細胞株,HCT116 野生型和HCT116 p53-/-細胞株並無細胞凋亡產生,然而p21-/-細胞株則隨著 clozapine處理的濃度升高,ROS表現量上昇且細胞凋亡產生越明顯。在HCT116野生型細胞株,處理抗氧化劑vitamin E (-Tocopherol)減少ROS,同時也降低p21蛋白表現,此結果顯示clozapine增加ROS而導致p21蛋白的表現量上升。進一步的結果也顯示p21蛋白牽涉ROS可能與活化抗氧化反應的轉錄因子Nrf2有關,是否clozapine導致細胞凋亡是透過p21及Nrf2調控ROS則有待進一步的研究。
Clinical studies have shown that patients with schizophrenia have a lower cancer incidence than the general population. Several antipsychotics have been demonstrated to confer cytotoxic effects on cancer cells, but the detailed molecular mechanism is unclear. Abnormal activation of the Wnt/β-catenin pathway plays an important role in colorectal cancer. In this study, two human colorectal cancer cell lines, HCT116 and SW480, were used to investigate the effect of clozapine, an antipsychotic widely used to treat patient with refractory schizophrenia, on Wnt/β-catenin pathway. Preliminary data showed that clozapine inhibited proliferation of SW480 and HCT116 cells in time- and dosage-dependent manners. Clozapine suppressed -catenin mRNA and protein levels. Furthermore, clozapine also decreased the expression of β-catenin downstream target gene cyclin D1. These results suggested that clozapine inhibited the growth of colorectal cancer cells through the inhibition of β-catenin transcription. On the other topic, our previous results revealed that clozapine increased p21 protein expression and reactive oxygen species (ROS) in HCT116 cancer cells. Studies have shown that p21 protects cells against oxidative stress. Here, we examined the relationship between clozapine-induced ROS and p21. Clozapine inhibited cell proliferation and colony formation via p53-independent manner and HCT116 p21-/- cells were more sensitive to clozapine. Clozapine increased more ROS and induced apoptosis in HCT116 p21-/- cells compared to HCT116 cells. In HCT116 cells, a ROS scavenger vitamin E (α-Tocopherol) decreased ROS, but also reduced p21 protein expression. The results showed that clozapine-increased ROS caused p21 protein expression. Furthermore, we also demonstrated that p21-mediated ROS is associated with Nrf2, a transcription factor can activate an antioxidant response to decrease ROS. It needs to further verify whether clozapine induces apoptosis via p21 and Nrf2 to control ROS levels.
URI: http://ethesys.lib.ntou.edu.tw/cdrfb3/record/#G0010036025
Appears in Collections:[生命科學暨生物科技學系] 博碩士論文

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