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CD29 and CD7 Mediate Galectin-3-Induced Type II T-Cell Apoptosis

¹ Tumor Progression and Metastasis Program, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan;
² Department of Urology, The University of Tokushima School of Medicine, Tokushima, Japan;
³ Department of Otolaryngology and Sensory Organ Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; and
⁴ Department of Pathology, Wayne State University, School of Medicine, Detroit, Michigan

Galectin (Gal)-3, a M_r 31,000 member of the ß-galactoside-binding protein family, is a multifunctional protein implicated in a variety of biological functions, including tumor cell adhesion, proliferation, differentiation, angiogenesis, apoptosis, cancer progression, and metastasis. Here, we report that secreted extracellular Gal-3 can signal apoptosis of human T leukemia cell lines, human peripheral blood mononuclear cells, and activated mouse T cells after binding to cell surface glycoconjugate receptors through carbohydrate-dependent interactions because the apoptotic effect was found to be inhibited by lactose, specific sugar inhibitor, and to be dose dependent. However, the apoptosis sensitivity to Gal-3 varied among the different cell lines tested. We report that Gal-3-null Jurkat, CEM, and MOLT-4 cells were significantly more sensitive to exogenous Gal-3 than SKW6.4 and H9 cells, which express Gal-3, suggesting a cross-talk between the antiapoptotic activity of intracellular Gal-3 and proapoptotic activity of extracellular Gal-3. Furthermore, Gal-3-transfected CEM cells were found to be more resistant to C₂-ceramide-induced apoptosis than the control CEM cells. Identification of Gal-3 cell surface receptors revealed that Gal-3 binding to CD7 and CD29 (ß₁ integrin) induced apoptosis. Gal-3 binding to its cell surface receptors results in activation of mitochondrial apoptosis events including cytochrome c release and caspase-3 activation, but not caspase-8 activation. Taken together, these results suggest that the induction of T-cell apoptosis by secreted Gal-3 may play a role in the immune escape mechanism during tumor progression through the induction of apoptosis to cancer-infiltrating T cells. The induction of T-cell apoptosis by secreted Gal-3 is dependent in part on the presence or absence of cytoplasmic Gal-3, providing a new insight for the immune escape mechanism of cancer cells.

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