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Cell Cycle Arrest and Inhibition of Anoikis by Galectin-3 in Human Breast Epithelial Cells¹

Department of Pathology [H-R. C. K., H-M. L., H. B., A. R.], Breast Cancer Program [H-R. C. K.], Tumor Progression and Metastasis Program [A. R.], Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, Michigan 48201

Galectin-3 is a member of a growing family of animal ß-galactoside-binding proteins shown to be involved in cell growth, differentiation, apoptosis resistance, and tumor progression. In the present study, we investigated whether galectin-3 can protect against apoptosis induced by the loss of cell anchorage (anoikis). Because studies suggest that cellular sensitivity to anoikis is associated with cell cycle regulation, we examined the role of galectin-3 on cell cycle regulation. Although BT549 cells (human breast epithelial cells) undergo anoikis, galectin-3-overexpressing BT549 cells respond to the loss of cell adhesion by inducing G₁ arrest without detectable cell death. Galectin-3-mediated G₁ arrest involves down-regulation of G₁-S cyclin levels (cyclin E and cyclin A) and up-regulation of their inhibitory protein levels (p21^WAF1/CIP1 and p27^KIP1). After the loss of cell anchorage, Rb protein becomes hypophosphorylated in galectin-3-overexpressing cells, as predicted from the flow cytometric analysis and immunoblot analysis of cyclins and their inhibitors. Interestingly, galectin-3 induces cyclin D₁ expression (an early G₁ cyclin) and its associated kinase activity in the absence of cell anchorage. On the basis of these results, we propose that galectin-3 inhibition of anoikis involves cell cycle arrest at an anoikis-insensitive point (late G₁) through modulation of gene expression and activities of cell cycle regulators. The present study suggests that galectin-3 may be a critical determinant for anchorage-independent cell survival of disseminating cancer cells in the circulation during metastasis.

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