Phosphatidylinositol 3-kinase/Akt activation by integrin-tumor matrix interaction suppresses Fas-mediated apoptosis in T cells.
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 beta 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-x(L) 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-x(L) cleavage as well as decreasing the phosphorylation of Bad at serine 136. Together, our results indicate that stimulation of the beta 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.
Su
Chung-Chen
CC
Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan, Republic of China.
Lin
Yu-Ping
YP
Cheng
Yu-Jung
YJ
Huang
Jyun-Yuan
JY
Chuang
Woei-Jer
WJ
Shan
Yan-Shen
YS
Yang
Bei-Chang
BC
D000818:Animals; D000906:Antibodies / Q000276:immunology; D017209:Apoptosis; D002460:Cell Line; D018920:Coculture Techniques; D004789:Enzyme Activation; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D051025:bcl-Associated Death Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism*
D000906:Antibodies; C481004:CH-11 anti-fas antibody, human; D016023:Integrins; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D019014:fas Receptor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases