title: The chemopreventive bioflavonoid apigenin inhibits prostate cancer cell motility through the focal adhesion kinase/Src signaling mechanism.
abstract: Prostate cancer mortality is primarily attributed to metastatic rather than primary, organ-confined disease. Acquiring a motile and invasive phenotype is an important step in development of tumors and ultimately metastasis. This step involves remodeling of the extracellular matrix and of cell-matrix interactions, cell movement mediated by the actin cytoskeleton, and activation of focal adhesion kinase (FAK)/Src signaling. Epidemiologic studies suggest that the metastatic behavior of prostate cancer may be an ideal target for chemoprevention. The natural flavone apigenin is known to have chemopreventive properties against many cancers, including prostate cancer. Here, we study the effect of apigenin on motility, invasion, and its mechanism of action in metastatic prostate carcinoma cells (PC3-M). We found that apigenin inhibits PC3-M cell motility in a scratch-wound assay. Live cell imaging studies show that apigenin diminishes the speed and affects directionality of cell motion. Alterations in the cytoskeleton are consistent with impaired cell movement in apigenin-treated cells. Apigenin treatment leads to formation of "exaggerated filopodia," which show accumulation of focal adhesion proteins at their tips. Furthermore, apigenin-treated cells adhere more strongly to the extracellular matrix. Additionally, apigenin decreases activation of FAK and Src, and phosphorylation of Src substrates FAK Y576/577 and Y925. Expression of constitutively active Src blunts the effect of apigenin on cell motility and cytoskeleton remodeling. These results show that apigenin inhibits motility and invasion of prostate carcinoma cells, disrupts actin cytoskeleton organization, and inhibits FAK/Src signaling. These studies provide mechanistic insight into developing novel strategies for inhibiting prostate cancer cell motility and invasiveness.
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Carrie A
authors.initials: CA
authors.lastname: Franzen
authors.forename: Evangeline
authors.initials: E
authors.lastname: Amargo
authors.forename: Viktor
authors.initials: V
authors.lastname: Todorović
authors.forename: Bhushan V
authors.initials: BV
authors.lastname: Desai
authors.forename: Sabil
authors.initials: S
authors.lastname: Huda
authors.forename: Salida
authors.initials: S
authors.lastname: Mirzoeva
authors.forename: Karen
authors.initials: K
authors.lastname: Chiu
authors.forename: Bartosz A
authors.initials: BA
authors.lastname: Grzybowski
authors.forename: Teng-Leong
authors.initials: TL
authors.lastname: Chew
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Green
authors.forename: Jill C
authors.initials: JC
authors.lastname: Pelling
mesh_terms: D000199:Actins / Q000378:metabolism / Q000648:ultrastructure; D047310:Apigenin / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects / Q000648:ultrastructure; D004789:Enzyme Activation / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D011554:Pseudopodia / Q000187:drug effects; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured; D014945:Wound Healing / Q000187:drug effects
chemical_list: D000199:Actins; D047310:Apigenin; D051416:Focal Adhesion Protein-Tyrosine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src)