Preferential dependence of breast cancer cells versus normal cells on integrin-linked kinase for protein kinase B/Akt activation and cell survival.

Abstract

The emerging paradigm of "oncogene addiction" has been called an Achilles' heel of cancer that can be exploited therapeutically. Here, we show that integrin-linked kinase (ILK), which is either activated or overexpressed in many types of cancers, is a critical regulator of breast cancer cell survival through the protein kinase B (PKB)/Akt pathway but is largely dispensable for the survival of normal breast epithelial cells and mesenchymal cells. We show that inhibition of ILK activity with a pharmacologic ILK inhibitor, QLT-0267, results in the inhibition of PKB/Akt Ser473 phosphorylation, stimulation of apoptosis, and a decrease in mammalian target of rapamycin (mTOR) expression in human breast cancer cells. In contrast, QLT-0267 treatment has no effect on PKB/Akt Ser473 phosphorylation or apoptosis in normal human breast epithelial, mouse fibroblast, or vascular smooth muscle cells. The inhibition of PKB/Akt Ser473 phosphorylation by QLT-0267 in breast cancer cells was rescued by a kinase-active ILK mutant but not by a kinase-dead ILK mutant. Furthermore, a dominant-negative ILK mutant increased apoptosis in the MDA-MB-231 breast cancer cell line but not in normal human breast epithelial cells. The inhibitor was active against ILK isolated from all cell types but did not have any effect on cell attachment and spreading. Our data point to an "ILK addiction" of breast cancer cells whereby they become dependent on ILK for cell survival through the mTOR-PKB/Akt signaling pathway and show that ILK is a promising target for the treatment of breast cancer.

• Authors: Armelle A Troussard, Paul C McDonald, Elizabeth D Wederell, Nasrin M Mawji, Nolan R Filipenko, Karen A Gelmon, Jill E Kucab, Sandra E Dunn, Joanne T Emerman, Marcel B Bally, Shoukat Dedhar
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 1 Pg. 393-403 (Jan 01 2006) ISSN: 0008-5472 [Print] United States
• PMID: 16397254 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Kinase Inhibitors
• Protein Kinases
• integrin-linked kinase
• MTOR protein, human
• mTOR protein, mouse
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Amino Acid Sequence
• Animals
• Apoptosis (drug effects, physiology)
• Breast (enzymology)
• Breast Neoplasms (enzymology, pathology)
• Cell Line, Tumor
• Cell Survival (physiology)
• Enzyme Activation
• Epithelial Cells (enzymology)
• Humans
• Male
• Mesoderm (cytology, enzymology)
• Mice
• Molecular Sequence Data
• NIH 3T3 Cells
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology)
• Protein Kinases (biosynthesis, metabolism)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• TOR Serine-Threonine Kinases