Phosphatidylinositol 3-kinase/Akt activation by integrin-tumor matrix interaction suppresses Fas-mediated apoptosis in T cells

Chung Chen Su, Yu Ping Lin, Yu Jung Cheng, Jyun Yuan Huang, Woei-Jer Chuang, Yan-Shen Shan, Bei-Chang Yang

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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-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 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.

Original languageEnglish
Pages (from-to)4589-4597
Number of pages9
JournalJournal of Immunology
Volume179
Issue number7
DOIs
Publication statusPublished - 2007 Oct 1

Fingerprint

Phosphatidylinositol 3-Kinase
Integrins
Apoptosis
T-Lymphocytes
Jurkat Cells
Neoplasms
p38 Mitogen-Activated Protein Kinases
Phosphatidylinositol 3-Kinases
Death Domain Receptor Signaling Adaptor Proteins
Phosphorylation
MAP Kinase Kinase 4
MAP Kinase Kinase Kinases
Fas Ligand Protein
Caspase 8
Coculture Techniques
Cyclic AMP-Dependent Protein Kinases
Tumor Cell Line
Cell Communication
Caspase 3
Membrane Potentials

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

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title = "Phosphatidylinositol 3-kinase/Akt activation by integrin-tumor matrix interaction suppresses Fas-mediated apoptosis in T cells",
abstract = "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-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 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.",
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Phosphatidylinositol 3-kinase/Akt activation by integrin-tumor matrix interaction suppresses Fas-mediated apoptosis in T cells. / Su, Chung Chen; Lin, Yu Ping; Cheng, Yu Jung; Huang, Jyun Yuan; Chuang, Woei-Jer; Shan, Yan-Shen; Yang, Bei-Chang.

In: Journal of Immunology, Vol. 179, No. 7, 01.10.2007, p. 4589-4597.

Research output: Contribution to journalArticle

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