Phosphatidylinositol 3-Kinase/Akt Activation by Integrin-Tumor Matrix Interaction Suppresses Fas-Mediated Apoptosis in T Cells
| Autor: | Chung Chen Su, Yu Jung Cheng, Jyun Yuan Huang, Bei Chang Yang, Yu Ping Lin, Yan Shen Shan, Woei Jer Chuang |
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| Rok vydání: | 2007 |
| Předmět: |
Integrins
Cell signaling T-Lymphocytes Immunology bcl-X Protein Apoptosis Biology Jurkat cells Antibodies Fas ligand Cell Line Mice Phosphatidylinositol 3-Kinases Neoplasms Animals Humans Immunology and Allergy fas Receptor Phosphorylation Protein kinase A Protein kinase B PI3K/AKT/mTOR pathway Kinase Coculture Techniques Cell biology Enzyme Activation bcl-Associated Death Protein Mitogen-Activated Protein Kinases Proto-Oncogene Proteins c-akt |
| Zdroj: | The Journal of Immunology. 179:4589-4597 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.179.7.4589 |
| Popis: | It has recently become apparent that the microenvironment made up of the extracellular matrix may affect cell signaling. In this study, we evaluated Fas-triggered apoptosis in T cells in contact with tumor cells, which resembles the cell-to-cell interactions found in tumor regions. Jurkat cells were less susceptible to the Fas-mediated apoptosis when cocultured with U118, HeLa, A549, and Huh-7 tumor cells. This was indicated by less plasma membrane alteration, an amelioration of the loss of mitochondria membrane potential, a decrease in caspase-8 and caspase-3 activation, a decrease in DNA fragmentation factor-45/35 cleavage, and a reduction in the breakage of DNA when compared with Jurkat cells cultured alone. In contrast, the tumor cell lines MCF-7 and HepG2 produced no such protective effect. This protective event was independent of the expression of Fas ligand on the tumor cells. Interrupting the β integrins-matrix interaction diminished the coculture effect. In Jurkat cells, cell matrix contact reduced the assembly of the Fas death-inducing signaling complex and Bcl-xL cleavage, but enhanced the phosphorylation of ERK1/2, p38 MAPK, and Akt. Only PI3K inhibitor, but not kinase inhibitors for MEK, ERK1/2, p38 MAPK, JNK, protein kinase C, and protein kinase A, completely abolished this tumor cell contact-associated protection and in parallel restored Fas-induced Bcl-xL cleavage as well as decreasing the phosphorylation of Bad at serine 136. Together, our results indicate that stimulation of the β integrin signal of T cells by contact with tumor cells may trigger a novel protective signaling through the PI3K/Akt pathway of T cells against Fas-mediated apoptosis. |
| Databáze: | OpenAIRE |
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