title: Down-regulation of 3-phosphoinositide-dependent protein kinase-1 levels inhibits migration and experimental metastasis of human breast cancer cells.
abstract: High expression of 3-phosphoinositide-dependent protein kinase-1 (PDK1) has been detected in various invasive cancers. In the current study, we investigated its role in cancer cell migration and experimental metastasis. Down-regulation of PDK1 expression by small interference RNA markedly inhibited spontaneous migration and epidermal growth factor (EGF)-induced chemotaxis of human breast cancer cells. The defects were rescued by expressing wild-type PDK1. PDK1-depleted cells showed impaired EGF-induced actin polymerization and adhesion, probably due to a decrease in phosphorylation of LIM kinase/cofilin and integrin beta1. Confocal microscopy revealed that EGF induced cotranslocation of PDK1 with Akt and protein kinase Czeta (PKCzeta), regulators of LIM kinase, and integrin beta1. Furthermore, PDK1 depletion dampened EGF-induced phosphorylation and translocation of Akt and PKCzeta, suggesting that Akt and PKCzeta functioned downstream of PDK1 in the chemotactic signaling pathway. In severe combined immunodeficiency mice, PDK1-depleted human breast cancer cells formed more slowly growing tumors and were defective in extravasation to mouse lungs after i.v. injection. Our results indicate that PDK1 plays an important role in regulating the malignant behavior of breast cancer cells, including their motility, through activation of Akt and PKCzeta. Thus, PDK1, which increases its expression in cancer cells, can be used as a target for the development of novel therapies.
authors.affiliation: Department of Chemical Biology, Peking University, Beijing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Jingna
authors.initials: J
authors.lastname: Wang
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.forename: Wuzhou
authors.initials: W
authors.lastname: Wan
authors.forename: Ronghua
authors.initials: R
authors.lastname: Sun
authors.forename: De
authors.initials: D
authors.lastname: Yang
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Sun
authors.forename: Dalong
authors.initials: D
authors.lastname: Ma
authors.forename: Guoguang
authors.initials: G
authors.lastname: Ying
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000199:Actins / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology; D015536:Down-Regulation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D051745:Protein Kinase C-delta / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D034741:RNA, Small Interfering; D004815:Epidermal Growth Factor; D064413:3-Phosphoinositide-Dependent Protein Kinases; C494921:AKT2 protein, human; C578562:PDPK1 protein, human; C578564:Pdpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D051745:Protein Kinase C-delta