CCL5增加肺癌細胞轉移經由PI3K, Akt 和 NF-κB路徑; CCL5 increases lung cancer migration via PI3K, Akt and NF-κB pathways

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Title:	CCL5增加肺癌細胞轉移經由PI3K, Akt 和 NF-κB路徑;CCL5 increases lung cancer migration via PI3K, Akt and NF-κB pathways
Authors:	黃俊寅;Chun-Yin Huang
Contributors:	中國醫藥大學：臨床醫學研究所碩士班
Keywords:	CCL5;肺癌細胞;細胞遷移;Akt;PI3K;Lung ancaer;Migration
Date:	2007-12-22
Issue Date:	2009-08-12 14:23:35 (UTC+8)
Abstract:	肺癌是全世界造成癌症死亡的主因，它時常在診斷時就已經發現有遠處的轉移。研究轉移的因素與機轉對疾病的治療是很重要的。趨化素(chemokines)在人類的發炎反應及癌細胞的遷移和轉移中扮演一個重要的角色。CCL5 (早期稱作RANTES)為 C-C趨化素的一員。先前的研究顯示，它與T細胞的活化和乳癌細胞的轉移有關。此外，integrins為細胞的主要黏著分子，與細胞的遷移有密不可分的關係。在本篇研究當中，我們探討CCL5對人類非小細胞肺癌細胞（A549細胞）中integrins的表現及其與遷移活性的影響。我們發現，CCL5可增加三株人類肺癌細胞(A549細胞、H929細胞和H1299細胞)的遷移，以及增加細胞表面αvβ3 integrin的表現。另外，肺癌細胞中CCR5的表現量也高於其他肺部表皮細胞(HBE-E6/E7 和 BEAS-2B)。更進一步，我們發現CCL5 的刺激會增加phosphatidylinositol 3-kinase(PI3K)中的p85α亞單位和Akt serine 473的磷酸化。而且，我們加PI3K 抑制劑 (Ly294002) 或者是Akt 的抑制劑，可抑制因CCL5 而產生的A549 細胞遷移活動，及A549 細胞integrin 的表現。用以p85顯性突變抑制物(dominant negative mutant)或者Akt顯性突變抑制物，也降低由於CCL5所引起的癌細胞轉移。另外，經CCL5處理過之A549細胞，會誘發IκB kinase α/β (IKK α/β)、IκB和 p65 Ser536磷酸化及κB-luciferase 的活性。最後，Ly294002 和Akt 抑制劑也抑制了CCL5調節的p65 Ser 536 磷酸化的增加。綜合上述，我們的結果顯示CCL5會經由PI3K/Akt的路徑，來活化IKK α/β和NF-κB以致αvβ3 integrin的表現，促使人類肺癌細胞的轉移。 Lung cancer is the leading cause of cancer-related mortality worldwide. It frequently results in distal metastases, including, brain, liver and bone marrow etc while it is diagnosed. Investigation of the factors and mechanism affecting tumor metastases is important in treatment of the disease. Chemokine plays a crucial role in the inflammatory response and the migration and metastasis of human cancer cells. CCL5 (previously called RANTES) is in the CC-chemokine family. Previous studies show it related with activation of T-cell and metastases of breast tumor cells. Besides, integrins are the major adhesive molecules in mammalian cells and important in the migration of cells. In this study, we examine the effect of CCL5 on integrin expression and migration activity in human non-small cell lung cancer cells. Here we found CCL5 increased the migration and cell surface expression of αvβ3 integrin in human lung cancer cells (A549 cells, H929 and H1299). The CCR5 of lung cancer cells have high expression than in lung epithelium cells (HBE-E6/E7 and BEAS-2B). Furthermore, we found CCL5 stimulation increased phosphorylation of the p85α subunit of phosphatidylinositol 3-kinase (PI3K) and serine 473 of Akt. Also, PI3K inhibitor (Ly294002) or Akt inhibitor suppressed CCL5-induced migration activities and integrin expression of A549 cells. Transfection of cells with p85 or Akt mutant also reduced CCL5-mediated cancer migration. In addition, treatment of A549 cells with CCL5 induced IκB kinase α/β?}??(IKK α/β) phosphorylation, IκB phosphorylation, p65 Ser536 phosphorylation, and κB-luciferase activity. Furthermore, the CCL5-mediated increases in p65 Ser536 phosphorylation were inhibited by Ly294002 and Akt inhibitor. Taken together, our results suggest that CCL5 acts through PI3K/Akt, which in turn activates IKK?悈/β and NF-κB, resulting in the activation of αvβ3 integrin and contributing to the migration of human lung cancer cells.
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