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Open Access Publications from the University of California

A Novel Mechanism of Apoptosis Resistance: The Interaction of Cell Surface Galectin-3 and CD45 Promotes Survival of Diffuse Large B Cell Lymphoma Cells

  • Author(s): Clark, Mary Caroline
  • Advisor(s): Baum, Linda G
  • et al.

Galectin-3 (gal-3) is a member of the galectin family of immunoregulatory lectins and has anti-apoptotic function. As an anti-apoptotic protein, gal-3 is upregulated and thought to contribute to apoptosis resistance in numerous types of cancer. One cancer in which gal-3 expression is upregulated is diffuse large B cell lymphoma (DLBCL), a cancer of germinal center and post-germinal center (activated) B cells. However, it is unknown whether the expression of gal-3 by DLBCL cells contributes to apoptosis resistance, and if it does, the mechanism by which gal-3 acts to promote DLBCL cell survival is also unknown. In this work, I have investigated whether and how gal-3 confers apoptosis resistance to DLBCL cells.

I have found that gal-3 binds to the transmembrane tyrosine phosphatase CD45 on DLBCL cells, and that removal of gal-3 from CD45 with the polyvalent glycan inhibitor GCS-100 was sufficient to render DLBCL cells susceptible to a variety of apoptotic stimuli. Mechanistically, gal-3 binding to CD45 modulated activity of the intracellular phosphatase domains of CD45; gal-3 binding to CD45 decreased phosphatase activity, while removal of gal-3 with GCS-100 increased phosphatase activity. Moreover, the increased activity of the CD45 phosphatase upon removal of gal-3 was required for DLBCL cells to undergo apoptosis. This suggests that gal-3 binding to CD45 is an upstream, reversible "apoptotic block" in DLBCL cells. Importantly, while the CD45 phosphatase of gal-3+ DLBCL cells could be activated by the removal of cell surface gal-3 from CD45 with GCS-100, the CD45 phosphatase of gal-3- DLBCL cells could not be activated by GCS-100 treatment. In fact, when evaluated as a prognostic factor in DLBCL, gal-3 expression correlated with better patient survival, possibly because gal-3+ DLBCL cells had "activatable" CD45 phosphatase, while the phosphatase activity of gal-3- DLBCL cells could not be enhanced. Together, these results identify a novel role for cell surface gal-3 and CD45 in DLBCL cell survival, and suggest novel therapeutic targets to sensitize DLBCL cells to apoptosis.

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