title: Protein kinase D2 is a novel regulator of glioblastoma growth and tumor formation.
abstract: Glioblastoma multiforme, a highly aggressive tumor of the central nervous system, has a dismal prognosis that is due in part to its resistance to radio- and chemotherapy. The protein kinase C (PKC) family of serine threonine kinases has been implicated in the formation and proliferation of glioblastoma multiforme. Members of the protein kinase D (PKD) family, which consists of PKD1, -2 and, -3, are prominent downstream targets of PKCs and could play a major role in glioblastoma growth. PKD2 was highly expressed in both low-grade and high-grade human gliomas. The number of PKD2-positive tumor cells increased with glioma grading (P < .001). PKD2 was also expressed in CD133-positive glioblastoma stem cells and various glioblastoma cell lines in which the kinase was found to be constitutively active. Inhibition of PKDs by pharmacological inhibitors resulted in substantial inhibition of glioblastoma proliferation. Furthermore, specific depletion of PKD2 by siRNA resulted in a marked inhibition of anchorage-dependent and -independent proliferation and an accumulation of glioblastoma cells in G0/G1, accompanied by a down-regulation of cyclin D1 expression. In addition, PKD2-depleted glioblastoma cells exhibited substantially reduced tumor formation in vivo on chicken chorioallantoic membranes. These findings identify PKD2 as a novel mediator of glioblastoma cell growth in vitro and in vivo and thereby as a potential therapeutic target for this devastating disease.
authors: Department of Internal Medicine l, Medical University of Ulm, Germany.
authors: Ninel
authors: N
authors: Azoitei
authors: Alexander
authors: A
authors: Kleger
authors: Nina
authors: N
authors: Schoo
authors: Dietmar Rudolf
authors: DR
authors: Thal
authors: Cornelia
authors: C
authors: Brunner
authors: Ganesh Varma
authors: GV
authors: Pusapati
authors: Alina
authors: A
authors: Filatova
authors: Felicitas
authors: F
authors: Genze
authors: Peter
authors: P
authors: Möller
authors: Til
authors: T
authors: Acker
authors: Rainer
authors: R
authors: Kuefer
authors: Johan
authors: J
authors: Van Lint
authors: Heinrich
authors: H
authors: Baust
authors: Guido
authors: G
authors: Adler
authors: Thomas
authors: T
authors: Seufferlein
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001921:Brain / Q000201:enzymology*; D001932:Brain Neoplasms / Q000201:enzymology / Q000473:pathology*; D002453:Cell Cycle; D049109:Cell Proliferation; D002645:Chickens; D049033:Chorioallantoic Membrane / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D005909:Glioblastoma / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques; D034741:RNA, Small Interfering / Q000235:genetics; D050396:TRPP Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D019938:Cyclin D1; D034741:RNA, Small Interfering; D050396:TRPP Cation Channels; C530104:CCND1 protein, human