NGAL decreases E-cadherin-mediated cell-cell adhesion and increases cell motility and invasion through Rac1 in colon carcinoma cells

Expression of neutrophil gelatinase-associated lipocalin (NGAL)/lipocalin2, a recently recognized iron regulatory protein that bonds to matrix metalloproteinase 9 (MMP9), is increased in a spectrum of cancers including those of the colorectum. Using colon carcinoma cell lines stably transfected with NGAL or antisense NGAL, we demonstrated that NGAL overexpression altered subcellular localization of E-cadherin and catenins, decreased E-cadherin-mediated cell-cell adhesion, enhanced cell-matrix attachment, and increased cell motility and in vitro invasion. Conversely, decrease in NGAL enhanced more aggregated growth pattern and decreased in vitro invasion. We further demonstrated that NGAL exerted these effects through alteration of the subcellular localization of Rac1 in an extracellular matrix-dependent but MMP9-independent manner. Furthermore, we observed that the NGAL overexpressing cells tolerated increased iron level in the culture environment while the NGAL underexpressing cells showed significant cell death after prolonged incubation in high iron condition. Thus, overexpressing NGAL in colon carcinomas is an important regulatory molecule that integrates extracellular environment cues, iron metabolism, and intracellular small GTPase signaling in cancer migration and invasion. NGAL may therefore be a new target for therapeutic intervention in colorectal carcinoma.