CCL5增加肺癌細胞轉移經由PI3K, Akt 和 NF-κB路徑

Abstract

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.