五氟利多的再利用-藉由自噬體堆積及阻斷基質金屬蛋白酶-12調控之上皮間質轉化等機制來抑制肺癌細胞之研究

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題名:	五氟利多的再利用-藉由自噬體堆積及阻斷基質金屬蛋白酶-12調控之上皮間質轉化等機制來抑制肺癌細胞之研究 Restrain lung cancer by repurposing penfluridol via autophagosome accumulation and blocking of MMP-12 modulated-epithelial-mesenchymal transition
作者:	洪文岳 HUNG, WEN-YUEH
貢獻者:	臨床醫學研究所博士班簡銘賢鍾啟禮
關鍵詞:	五氟利多;非小細胞肺癌;自噬體堆積;內質網壓力;未折疊蛋白反應;基質金屬蛋白酶-12;上皮間質轉化 Penfluridol;non-small-cell lung cancer;autophagosome accumulation;endoplasmic reticulum stress;unfolded protein response;matrix metalloproteinase -12;epithelial–mesenchymal transition
日期:	2022-01-11
上傳時間:	2022-08-09 10:49:01 (UTC+8)
摘要:	細胞凋亡 (apoptosis) 誘導機制的缺陷及上皮間質轉化 (epithelial–mesenchymal transition, EMT) 乃是腫瘤進展惡化的特徵。目前已發現重新利用抗精神病藥五氟利多 (penfluridol) 可有效抑制多種癌症的生長，但五氟利多對肺癌的治療效果仍然未知。我們發現，五氟利多在 > 5 μM的濃度下，對於不同表皮生長因子受體 (epidermal growth factor receptor, EGFR) 突變狀態的各種非小細胞肺癌 (Non-small cell lung cancer, NSCLC) 細胞具有細胞毒性。五氟利多在非細胞毒性的濃度下 (1.25-2.5 μM) 對非小細胞肺癌細胞顯示出抑制遷移、侵襲和粘附等作用。這些抗腫瘤生長和轉移作用在非小細胞肺癌的原位異種移植模型中也得到證實。在機制上，五氟利多在具有細胞毒性的濃度下，藉由阻斷自噬流 (autophagic flux) 並誘導自噬體相關蛋白輕鏈 3 (LC3) B-II 的積累來誘導非凋亡細胞死亡 (non-apoptotic cell death)。自噬體的堆積 (autophagosome accumulation) 導致的細胞死亡主要歸因於ATP的喪失。再進一步探究其機制，內質網壓力 (ER-stress) 引起的未折疊蛋白反應unfolded protein response (UPR) 路徑的活化和 p38 絲裂原活化蛋白激酶 (mitogen-activated protein kinase, MAPK) 的激活對五氟利多引起的自噬體的堆積至關重要。至於非細胞毒性的抗轉移機制，是藉由抑制尿激酶纖溶酶原激活劑/尿激酶纖溶酶原激活劑受體/乙型轉化生長因子/蛋白激酶B軸 (uPA/uPA receptor/ transforming growth factor-β/Akt axis)以減少MMP-12之表達，進而抑制 MMP-12 誘導的EMT。在臨床數據上，我們亦觀察到當肺腫瘤有較高的LC3B或MMP-12之表現量時，患者在對應上有較長或較短的生存時間。五氟利多在臨床上用於精神分裂症，我們的研究結果強烈支持五氟利多可作為治療非小細胞肺癌的再利用藥物。 Defective apoptosis induction and epithelial–mesenchymal transition (EMT) are hallmarks of tumor progression. Repurposing of the antipsychotic agent penfluridol has been reported to retard the progression of various cancers, but the therapeutic potential of penfluridol on lung cancer remains unknown. Herein, the cytotoxic effect of penfluridol (> 5 μM) was demonstrated in various non-small-cell lung cancer (NSCLC) cell lines harboring different epidermal growth factor receptor (EGFR) mutation statuses. Nontoxic concentrations of penfluridol (1.25-2.5 μM) showed the anti-migratory, invasive, and adhesive effects in NSCLC cells. These antitumor growth and metastasis effects were also observed in a NSCLC orthotopic xenograft model. Mechanistically, cytotoxic concentration of penfluridol induced nonapoptotic cell death by blocking autophagic flux and inducing accumulation of autophagosome-related protein, light chain 3 (LC3) B-II. Autophagosome accumulation-mediated cell death was mainly attributed to ATP energy deprivation. Moreover, upregulation of endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) pathways and activation of p38 mitogen-activated protein kinase (MAPK) were critical for penfluridol-induced autophagosome accumulation. Anti-metastatic effects of nontoxic penfluridol was attributed to inhibition of matrix metalloproteinase-12 (MMP-12)- induced epithelial–mesenchymal transition (EMT) via suppressing the urokinase plasminogen activator (uPA)/uPA receptor/transforming growth factor-beta/Akt axis. In clinic, we observed that patients with lung tumors expressing high LC3B and MMP-12 respectively had longer and shorter overall survival times. Penfluridol is clinically used for schizophrenia, and our study results strongly support penfluridol as a repurposed drug for treating NSCLC.
描述:	博士指導教授:簡銘賢共同指導教授:鍾啟禮委員:簡銘賢委員:鍾啟禮委員:湯智昕委員:華國泰委員:楊順發
資料類型:	thesis
顯示於類別:	[臨床醫學研究所] 博碩士論文

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