Cell cycle arrest and inhibition of anoikis by galectin-3 in human breast epithelial cells.
Galectin-3 is a member of a growing family of animal beta-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 p27KIP1). 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.
Kim
H R
HR
Department of Pathology, Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, Michigan 48201, USA. hrckim@med.wayne.edu
Lin
H M
HM
Biliran
H
H
Raz
A
A
D000943:Antigens, Differentiation / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001940:Breast / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects*; D002460:Cell Line; D004847:Epithelial Cells / Q000187:drug effects* / Q000473:pathology; D005260:Female; D037502:Galectin 3; D006801:Humans
D000943:Antigens, Differentiation; D037502:Galectin 3