左旋硒代胱胺酸抑制Nrf2與細胞自噬訊息途徑導致Nrf2成癮的結直腸癌細胞死亡

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徐偉倫(Wei-Lun Hsu) 查詢紙本館藏

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論文名稱

左旋硒代胱胺酸抑制Nrf2與細胞自噬訊息途徑導致Nrf2成癮的結直腸癌細胞死亡
(L-Selenocystine inhibit Nrf2 and autophagy pathway leading to cell death in Nrf2-addicted colorectal cancer cells)

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至系統瀏覽論文 (2027-7-11以後開放)

摘要(中)

結直腸癌為全世界目前好發率高的癌症之一，治療方法通常以手術、化學治療和放射線治療為主，但對後期轉移的病人通常效果不佳，因此臨床上需要及時開發其他有效的新型抗癌藥物進行治療。Nuclear factor erythroid 2–related factor 2 (Nrf2)可以調控癌細胞氧化壓力平衡與物質代謝。研究顯示癌細胞有Nrf2高度活化的現象，在生存和增生對 Nrf2 有高度依賴性，稱為 Nrf2 成癮。而具有Nrf2成癮特徵的癌細胞容易發展出抗藥性，造成癌症化療效果不佳且容易復發，因此針對Nrf2的抗癌藥物極有機會能有效抑制Nrf2 成癮癌細胞的生長。在本篇研究中，我們主要探討左旋硒代胱胺酸 (L-selenocystine, SeC) 對Nrf2成癮大腸癌細胞的抗癌作用。我們比較人類間質幹細胞 (Mesenchymal stem cell, MSC) 與結直腸癌細胞 (WiDr 和 C2BBe1)中其Nrf2與Nrf2相關蛋白質表現量，WiDr細胞具有Nrf2成癮的特徵，MSC細胞為非Nrf2成癮的細胞，而C2BBe1細胞則介於兩者之間，而SeC對WiDr細胞具有較高的細胞毒性與氧化壓力，但對MSC細胞則無明顯的細胞死亡。SeC會減少WiDr細胞的Nrf2/Keap1/p62訊號途徑相關蛋白質表現，而SeC則可正常活化MSC細胞的Nrf2與其下游反應。SeC誘導WiDr細胞中細胞質與粒線體的超氧陰離子產生，但在C2BBe1細胞的超氧陰離子並無明顯增加。抗氧化劑能有效恢復SeC造成的細胞死亡並抑制氧化壓力生成，同時能回復Nrf2/Keap1/p62訊號途徑受SeC的抑制。同時我們也發現WiDr細胞之細胞自噬相關蛋白質在SeC處理後表現量也明顯下降，相反地，SeC可活化MSC細胞之細胞自噬途徑。因此，我們利用細胞自噬抑制劑與SeC共同處裡WiDr細胞釐清細胞自噬的角色，結果顯示抑制細胞自噬會加劇SeC引起的細胞死亡，而抗氧化劑則能夠部分回復WiDr細胞自噬相關蛋白質受SeC影響之表現量。而而C2BBe1細胞的Nrf2蛋白質表現量比WiDr細胞相較低，受SeC影響也比WiDr細胞緩慢，Nrf2/Keap1/p62訊號途徑與細胞自噬途徑需要較長的時間反應才有明顯抑制。我們利用siRNA減少C2BBe1細胞的Keap1表現以提高其Nrf2的活性，模擬類似Nrf2成癮的狀態，結果顯示減少Keap1表現的細胞對SeC的敏感性增加，細胞毒性與氧化壓力產生均有顯著提高。相反地，利用siRNA減少WiDr細胞的Nrf2蛋白質表現，發現處裡SeC的細胞存活率有回復的趨勢。總結來說，SeC能有效抑制Nrf2成癮細胞的Nrf2/Keap1/p62訊號途徑與細胞自噬的形成，並產生大量的氧化壓力分子，破壞氧化壓力平衡誘導細胞死亡。

摘要(英)

Colorectal cancer is one of the common cancers around the world. The therapy strategy for colorectal cancer is mainly dependent on surgery combined with chemotherapy and radiotherapy, which is effective in the early stage of colorectal cancer but poorly effective in the metastasis stage. Hence, it’s in urgent need of discovery effective chemotherapy for colorectal cancer. Nuclear factor erythroid 2–related factor 2 (Nrf2) regulates oxidative homeostasis and metabolic process in cancer cells Evidence has shown that tumor cells highly depend on sustained activation of Nrf2 for survival and proliferation, also known as Nrf2 addiction, which is associated with cancer cell metastasis and poor prognosis. Therefore, targeting Nrf2 is a promising therapeutic strategy for Nrf2-addicted cancers. In this study, we determined the anticancer effects of L-Selenocystine (SeC) in Nrf2-addicted colorectal cancer cells We compared the levels of Nrf2 and Nrf2-regulated proteins in mesenchymal stem cell (MSC), colorectal cancers (WiDr and C2BBe1). WiDr cells had Nrf2-addiction characteristics, and MSCs are the non-Nrf2-addicted cancers. Compared with WiDr cells, C2BBe1 cells express moderate levels of Nrf2 and Nrf2 regulated proteins. We found that SeC induced the highest cytotoxicity and ROS production in WiDr cells. After SeC treatment, Nrf2/Keap1/p62 pathway was inhibited in WiDr cells but activated in MSCs. Moreover, SeC treatment increased cytosolic and mitochondrial superoxides production in WiDr cells but not in C2BBe1 cells. Antioxidants decreased SeC-induced oxidative stress, rescued cytotoxicity of SeC, and increased levels of Nrf2-downstream proteins. Meanwhile, SeC treatment also decreased levels of autophagy proteins in WiDr cells but increased those in MSCs. We utilized autophagy inhibitors to clarify the role of autophagy in SeC-induced cell death. Autophagy inhibitor increased cell mortality in SeC-treated WiDr cells. Antioxidants partially recovered the expression of autophagy-associated proteins in SeC-treated WiDr cells. C2BBe1 cells had lower levels of Nrf2 which show a slower cytotoxic effect and Nrf2/Keap1/P62 inhibition comparison with those of in WiDr cells after SeC treatment. We utilized siRNA transfection to knock down Keap1 to mimic Nrf2 addicted status, the sensitivity to SeC and ROS production were increased in SeC-treated C2BBe1 cells. However, Nrf2 knockdown recovers the cell viability after treatment in WiDr cells. In summary, our results indicated that SeC effectively inhibits Nrf2 and autophagy pathway, and triggers oxidative stress, leading to cell death in Nrf2-addicted cancer cells.

關鍵字(中)

★ 結直腸癌
★ 左旋硒代胱胺酸
★ 氧化壓力
★ 細胞自噬

關鍵字(英)

★ Nrf2

論文目次

中文摘要 I
英文摘要 II
致謝 IV
目錄 V
圖目錄 VIIII
縮寫檢索表 VIII
第一章緒論 1
1.1 結直腸癌 ( Colorectal Carcinoma, CRC ) 之發生與治療 1
1.2 Nuclear factor erythroid 2–related factor 2 (Nrf2) 之訊號途徑與癌細胞 Nrf2 成癮………………………………………………………………………...3
1.3 細胞自噬 (Autophagy) 之訊息傳導 7
1.4 左旋硒代胱胺酸 ( L-Selenocystine, SeC ) 9
第二章實驗材料及方法 12
2.1實驗材料 12
2.1.1實驗細胞株 12
2.1.2實驗材料 12
2.1.3 試劑 12
2.1.4. 耗材 15
2.1.5 儀器 15
2.2實驗方法 16
2.2.1細胞培養及處理方法 16
2.2.2細胞裂解液製備與蛋白質濃度測定 16
2.2.3西方墨點法 17
2.2.4硒代胱胺酸 (L-Selenocystine) 原液配製 19
2.2.5細胞存活率測試 (MTT assay, Thiazolyl Blue Tetrazolium Bromide)………………………………………………………………………..20
2.2.6氧化壓力測試 20
2.2.7超氧陰離子 ( O2- ) 之檢測 21
2.2.8免疫螢光染色 21
2.2.9細胞轉染 22
2.2.10作圖軟體與統計方法 23
第三章結果 25
3.1 SeC 影響 Nrf2 成癮的結直腸癌細胞的存活與氧化壓力累積 25
3.2 SeC 抑制 Nrf2 成癮的結直腸癌細胞之Nrf2/Keap1/p62 訊號途徑 26
3.3 SeC 誘導Nrf2成癮的癌細胞產生超氧陰離子 28
3.4 SeC藉由氧化壓力影響 Nrf2/Keap1/p62 訊號途徑 30
3.5 SeC抑制Nrf2 成癮的結直腸癌細胞之細胞自噬形成 32
3.6 C2BBe1細胞對SeC的敏感度和WiDr細胞相較低 34
3.7 Nrf2表現量影響SeC的細胞毒性與氧化壓力產生 35
第四章討論 37
第五章參考文獻 46
圖 53
附錄一 72

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指導教授

羅月霞(Yueh-Hsia Luo)

審核日期

2022-7-12

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