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標題: Imiquimod 在癌症細胞中所引起細胞自噬機制之探討
The Role of Imiquimod to Induce Autophagy in Cancer Cells
作者: 張書豪
Shu-Hao Chang
關鍵字: 細胞自噬
ER stress
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摘要: 細胞自噬(Autophagy)為高度保留性分解代謝之過程;當細胞處於營養缺乏及環境壓力下,細胞會藉由分解及回收胞內物質以產生能量,供應細胞生存所需。在生理及病理影響下,會導致錯誤摺疊或未摺疊蛋白質累積在內質網,破壞內質網的恆定性,造成內質網壓力(endoplasmic reticulum stress, ER stress)。Imiquimod (IMQ)為類鐸受體7、8 (Toll-like receptor 7、8,TLR7 and TLR8) 的配合體(ligand),在細胞及活體實驗中具有抗腫瘤及抗病毒之能力。有許多文獻指出IMQ會誘導細胞產生細胞自噬;近期也有文獻證明IMQ會促進巨噬細胞透過CHOP依賴性之細胞凋亡。然而,目前並未有文獻去作探討內質網壓力與IMQ誘導細胞自噬之關聯性;IMQ誘導之細胞自噬相關機制也尚末明確。在本研究中發現IMQ誘導癌細胞產生內質網壓力而造成細胞自噬的現象為PERK依賴性。利用內質網壓力抑制劑及基因靜默PERK都能有效地減少LC3-II表現及EGFP-LC3 puncta形成。IMQ能誘導癌細胞產生大量ROS而誘導內質網壓力產生進而造成細胞自噬的進行。IMQ可以活化PERK及PKR (double strand RNA-dependent protein kinase),而增加下游eIF2α磷酸化。利用PKR抑制劑或si-PKR都能有效地減少IMQ藉由PKR訊息傳遞所誘發之細胞自噬。我們也發現IMQ所造成內質網壓力可以活化PKR訊息傳遞。我們首先發現IMQ能誘發癌細胞產生大量ROS, 進而誘導內質網壓力之生成及活化PKR, 最後促進細胞自噬之進行。我們認為這些新穎的發現對於未來有關IMQ基礎或臨床上之研究,都能提供重要資訊。
Autophagy is a highly conserved cellular catabolic pathway for degradation and recycling intracellular components in response to nutrient starvation or environmental stresses. Endoplasmic reticulum (ER) homeostasis can be disturbed by physiological and pathological effects resulting an accumulation of misfolded and unfolded proteins in the ER lumen, a condition termed as ER stress. Imiquimod (IMQ), a Toll-like receptor (TLR) 7 and 8 ligand, contains antitumor and antiviral activity in vitro and in vivo. IMQ promotes the apoptosis of THP-1-derived macrophages through the ER stress-dependent pathway had been reported. However, the role of ER stress in IMQ-induced autophagy is unknown. In this study, we investigated the relationship between ER stress and IMQ-induced autophagy. We found that IMQ induced ROS production in cancer cells. Additionally, we found that IMQ markedly induced ER stress through ROS production and increased autophagosome formation in dose- and time-dependent manners in both TLR7/8 expressed and unexpressed cancer cells. Pharmacological and genetic inhibition of ER stress dramatically reduced LC3-II expression and EGFP-LC3 puncta formation in IMQ-treated cancer cells. IMQ-induced autophagy was also markedly reduced by depletion and/or inhibition of double strand RNA-dependent protein kinase (PKR), a downstream effector of ER stress. We suggested IMQ-induced autophagy is dependent on PKR activation which mediated by ROS triggered ER stress. We considered these findings might contribute useful information to basic and clinical research and application of IMQ.
文章公開時間: 10000-01-01
Appears in Collections:生物醫學研究所



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