FAK Inhibition disrupts a β5 integrin signaling axis controlling anchorage-independent ovarian carcinoma growth.

Abstract

Ovarian cancer ascites fluid contains matrix proteins that can impact tumor growth via integrin receptor binding. In human ovarian tumor tissue arrays, we find that activation of the cytoplasmic focal adhesion (FAK) tyrosine kinase parallels increased tumor stage, β5 integrin, and osteopontin matrix staining. Elevated osteopontin, β5 integrin, and FAK mRNA levels are associated with decreased serous ovarian cancer patient survival. FAK remains active within ovarian cancer cells grown as spheroids, and anchorage-independent growth analyses of seven ovarian carcinoma cell lines identified sensitive (HEY, OVCAR8) and resistant (SKOV3-IP, OVCAR10) cells to 0.1 μmol/L FAK inhibitor (VS-4718, formerly PND-1186) treatment. VS-4718 promoted HEY and OVCAR8 G0-G1 cell-cycle arrest followed by cell death, whereas growth of SKOV3-IP and OVCAR10 cells was resistant to 1.0 μmol/L VS-4718. In HEY cells, genetic or pharmacological FAK inhibition prevented tumor growth in mice with corresponding reductions in β5 integrin and osteopontin expression. β5 knockdown reduced HEY cell growth in soft agar, tumor growth in mice, and both FAK Y397 phosphorylation and osteopontin expression in spheroids. FAK inhibitor-resistant (SKOV3-IP, OVCAR10) cells exhibited anchorage-independent Akt S473 phosphorylation, and expression of membrane-targeted and active Akt in sensitive cells (HEY, OVCAR8) increased growth but did not create a FAK inhibitor-resistant phenotype. These results link osteopontin, β5 integrin, and FAK in promoting ovarian tumor progression. β5 integrin expression may serve as a biomarker for serous ovarian carcinoma cells that possess active FAK signaling.

• Authors: Isabelle Tancioni, Sean Uryu, Florian J Sulzmaier, Nina R Shah, Christine Lawson, Nichol L G Miller, Christine Jean, Xiao Lei Chen, Kristy K Ward, David D Schlaepfer
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 13 Issue 8 Pg. 2050-61 (Aug 2014) ISSN: 1538-8514 [Electronic] United States
• PMID: 24899686 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Aminopyridines
• Antineoplastic Agents
• Integrin beta Chains
• PND 1186
• integrin beta5
• Osteopontin
• Focal Adhesion Kinase 1
• PTK2 protein, human

Topics

• Aminopyridines (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Cell Adhesion
• Cell Line, Tumor
• Cell Proliferation
• Drug Resistance, Neoplasm
• Female
• Focal Adhesion Kinase 1 (antagonists & inhibitors, genetics, metabolism)
• Gene Knockdown Techniques
• Humans
• Integrin beta Chains (metabolism)
• Kaplan-Meier Estimate
• Mice, Nude
• Neoplasm Transplantation
• Neoplasms, Cystic, Mucinous, and Serous (metabolism, mortality)
• Osteopontin (metabolism)
• Ovarian Neoplasms (metabolism, mortality)
• Signal Transduction