Lactoferrin inhibits G1 cyclin-dependent kinases during growth arrest of human breast carcinoma cells

E Damiens; I El Yazidi; J Mazurier; I Duthille; G Spik; Y Boilly-Marer

Lactoferrin inhibits G1 cyclin-dependent kinases during growth arrest of human breast carcinoma cells

J Cell Biochem. 1999 Sep 1;74(3):486-98.

Authors

E Damiens¹, I El Yazidi, J Mazurier, I Duthille, G Spik, Y Boilly-Marer

Affiliation

¹ Laboratoire de Chimie Biologique, Unité Mixte de Recherche du CNRS no 8576, Université des Sciences et Technologies de Lille, 59655 Villeneuve d'Ascq Cedex, France.

PMID: 10412049

Abstract

Lactoferrin inhibits cell proliferation and suppresses tumor growth in vivo. However, the molecular mechanisms underlying these effects remain unknown. In this in vitro study, we demonstrate that treatment of breast carcinoma cells MDA-MB-231 with human lactoferrin induces growth arrest at the G1 to S transition of the cell cycle. This G1 arrest is associated with a dramatic decrease in the protein levels of Cdk2 and cyclin E correlated with an inhibition of the Cdk2 kinase activity. Cdk4 activity is also significantly decreased in the treated cells and is accompanied by an increased expression of the Cdk inhibitor p21(CIP1). Furthermore, we show that lactoferrin maintains the cell cycle progression regulator retinoblastoma protein pRb in a hypophosphorylated form. Additional experiments with synchronized cells by serum depletion confirm the anti-proliferative activity of human lactoferrin. These effects of lactoferrin occur through a p53-independent mechanism both in MDA-MB-231 cells and other epithelial cell lines such as HBL-100, MCF-7, and HT-29. These findings demonstrate that lactoferrin induces growth arrest by modulating the expression and the activity of key G1 regulatory proteins.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Breast Neoplasms / metabolism*
Breast Neoplasms / pathology
CDC2-CDC28 Kinases*
Cell Cycle / physiology
Cell Cycle Proteins*
Cell Division
Colonic Neoplasms / metabolism
Cyclin E / metabolism
Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase Inhibitor p16 / metabolism
Cyclin-Dependent Kinase Inhibitor p21
Cyclin-Dependent Kinase Inhibitor p27
Cyclin-Dependent Kinases / antagonists & inhibitors*
Cyclin-Dependent Kinases / metabolism
Cyclins / metabolism
Dose-Response Relationship, Drug
G1 Phase*
Humans
Lactoferrin / pharmacology*
Microtubule-Associated Proteins / metabolism
Protein Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins*
Thymidine / metabolism
Time Factors
Tumor Cells, Cultured
Tumor Suppressor Proteins*

Substances

CDKN1A protein, human
Cell Cycle Proteins
Cyclin E
Cyclin-Dependent Kinase Inhibitor p16
Cyclin-Dependent Kinase Inhibitor p21
Cyclins
Microtubule-Associated Proteins
Proto-Oncogene Proteins
Tumor Suppressor Proteins
Cyclin-Dependent Kinase Inhibitor p27
Protein Serine-Threonine Kinases
CDC2-CDC28 Kinases
CDK2 protein, human
CDK4 protein, human
Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinases
Lactoferrin
Thymidine