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* Institute of Basic Medical Sciences, Departments of
Microbiology and Immunology,
Biochemistry, and
Surgery, and
¶ Center for Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China
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 
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 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the National Science Council, Taiwan, Republic of China (NSC90-2320-B006-MB099 and NSC92-2320-B006-094) to B.-C.Y.
2 Address correspondence and reprint requests to Dr. Bei-Chang Yang, Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. E-mail address: y1357{at}mail.ncku.edu.tw
3 Abbreviations used in this paper: TIL, tumor-infiltrating lymphocyte; 
m, mitochondria transmembrane potential; AICD, activation-induced cell death; DFF, DNA fragmentation factor; DISC, death-inducing signaling complex; ECM, extracellular matrix; FasL, Fas ligand; oFas, overexpression of Fas.
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