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

Limei Hu, Walter Hittelman, Tao Lu, Ping Ji, Ralph Arlinghaus, Ilya Shmulevich, Stanley R. Hamilton, W. Zhang

Research output: Contribution to journalArticle

83 Scopus citations

Abstract

Expression of neutrophil gelatinase-associated lipocalin (NGAL)lipocalin2, a recently recognized iron regulatory protein that binds 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 showed that NGAL overexpression altered subcellular localization of E-cadherin and catenins, decreased E-cadherin-mediated cellcell adhesion, enhanced cellmatrix attachment, and increased cell motility and in vitro invasion. Conversely, a decrease in NGAL enhanced more aggregated growth pattern and decreased in vitro invasion. We further showed that NGAL exerted these effects through the 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 levels in the culture environment, whereas 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.

Original languageEnglish (US)
Pages (from-to)531-548
Number of pages18
JournalLaboratory Investigation
Volume89
Issue number5
DOIs
StatePublished - May 1 2009
Externally publishedYes

Keywords

  • Colon cancer
  • E-cadherin
  • Invasion
  • MMP9
  • NGAL
  • Rac1

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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