title: Phosphoinositide 3-kinase signaling pathway mediated by p110α regulates invadopodia formation.
abstract: Invadopodia are extracellular matrix-degrading protrusions formed by invasive cancer cells that are thought to function in cancer invasion. Although many invadopodia components have been identified, signaling pathways that link extracellular stimuli to invadopodia formation remain largely unknown. We investigate the role of phosphoinositide 3-kinase (PI3K) signaling during invadopodia formation. We find that in human breast cancer cells, both invadopodia formation and degradation of a gelatin matrix were blocked by treatment with PI3K inhibitors or sequestration of D-3 phosphoinositides. Functional analyses revealed that among the PI3K family proteins, the class I PI3K catalytic subunit p110α, a frequently mutated gene product in human cancers, was selectively involved in invadopodia formation. The expression of p110α with cancerous mutations promoted invadopodia-mediated invasive activity. Furthermore, knockdown or inhibition of PDK1 and Akt, downstream effectors of PI3K signaling, suppressed invadopodia formation induced by p110α mutants. These data suggest that PI3K signaling via p110α regulates invadopodia-mediated invasion of breast cancer cells.
authors.affiliation: Division of Metastasis and Invasion Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan. hidyamag@ncc.go.jp
authors.forename: Hideki
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Shuhei
authors.initials: S
authors.lastname: Yoshida
authors.forename: Emi
authors.initials: E
authors.lastname: Muroi
authors.forename: Nachi
authors.initials: N
authors.lastname: Yoshida
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kawamura
authors.forename: Zen
authors.initials: Z
authors.lastname: Kouchi
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Sakai
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Fukami
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000502:physiology*; D005260:Female; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction
chemical_list: D058543:Class Ia Phosphatidylinositol 3-Kinase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt