Focal Adhesion Kinase Controls Aggressive Phenotype of Androgen-Independent Prostate Cancer

• Published in: Molecular cancer research Vol. 6; no. 10; pp. 1639 - 1648
• Main Authors: Johnson, Thomas R, Khandrika, Lakshmipathi, Kumar, Binod, Venezia, Sarah, Koul, Sweaty, Chandhoke, Ryan, Maroni, Paul, Donohue, Robert, Meacham, Randall B, Koul, Hari K
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01-10-2008
• Subjects: Androgens - metabolism; Anoikis; Cell Line, Tumor; Cell Proliferation; Cell Survival; clonogenicity; Enzyme Activation; ERK; FAK; Focal Adhesion Protein-Tyrosine Kinases - metabolism; Humans; invasiveness; Male; MAP Kinase Signaling System; Matrix Metalloproteinase 9 - metabolism; Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 3 - metabolism; Neoplasm Invasiveness; Phenotype; Phosphorylation; prostate cancer; Prostatic Neoplasms - enzymology; Prostatic Neoplasms - pathology; RNA, Small Interfering - metabolism; RNAi; Tumor Stem Cell Assay
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-08-0052

Overexpression of focal adhesion kinase (FAK) has been well correlated with tumor development and/or the maintenance of tumor
phenotype. In addition, inappropriate activation of the extracellular regulated kinase (ERK) signaling pathway is common to
many human cancers. In the present study, we investigated the interplay between FAK and ERK in androgen-independent prostate
cancer cells (PC3 and DU145 cells). We observed that suppression of FAK expression using small interfering RNA–mediated knockdown
decreased the clonogenic activity, whereas overexpression of FAK increased it. We also observed that detachment of PC3 and
DU145 cells from their substrate induced tyrosine phosphorylation of FAK. ERK knockdown diminished FAK protein levels and
tyrosine phosphorylation of FAK as well as FAK promoter-reporter activity. We also tested the effect of MEK inhibitors and
small interfering RNA–mediated knockdown of ERK1 and/or ERK2 on cell proliferation, invasiveness, and growth in soft agar
of PC3 and DU145 cells. Inhibition of ERK signaling grossly impaired clonogenicity as well as invasion through Matrigel. However,
inhibition of ERK signaling resulted in only a modest inhibition of 3 H-thymidine incorporation and no effect on overall viability of the cells or increased sensitivity to anoikis. Taken together,
these data show, for the first time, a requirement for FAK in aggressive phenotype of prostate cancer cells; reveal interdependence
of FAK and ERK1/2 for clonogenic and invasive activity of androgen-independent prostate cancer cells; suggest a role for ERK
regulation of FAK in substrate-dependent survival; and show for the first time, in any cell type, the regulation of FAK expression
by ERK signaling pathway. (Mol Cancer Res 2008;6(10):1639–48)