Protein kinase C-alpha-mediated regulation of low-density lipoprotein receptor related protein and urokinase increases astrocytoma invasion.
Aggressive and infiltrative invasion is one of the hallmarks of glioblastoma. Low-density lipoprotein receptor-related protein (LRP) is expressed by glioblastoma, but the role of this receptor in astrocytic tumor invasion remains poorly understood. We show that activation of protein kinase C-alpha (PKC-alpha) phosphorylated and down-regulated LRP expression. Pretreatment of tumor cells with PKC inhibitors, phosphoinositide 3-kinase (PI3K) inhibitor, PKC-alpha small interfering RNA (siRNA), and short hairpin RNA abrogated phorbol 12-myristate 13-acetate-induced down-regulation of LRP and inhibited astrocytic tumor invasion in vitro. In xenograft glioblastoma mouse model and in vitro transmembrane invasion assay, LRP-deficient cells, which secreted high levels of urokinase-type plasminogen activator (uPA), invaded extensively the surrounding normal brain tissue, whereas the LRP-overexpressing and uPA-deficient cells did not invade into the surrounding normal brain. siRNA, targeted against uPA in LRP-deficient clones, attenuated their invasive potential. Taken together, our results strongly suggest the involvement of PKC-alpha/PI3K signaling pathways in the regulation of LRP-mediated astrocytoma invasion. Thus, a strategy of combining small molecule inhibitors of PKC-alpha and PI3K could provide a new treatment paradigm for glioblastomas.
Amos
Samson
S
Department of Pathology, University of Virginia Health System, Charlottesville, VA 22908, USA. sa7h@virginia.edu
Mut
Melike
M
diPierro
Charles G
CG
Carpenter
Joan E
JE
Xiao
Aizhen
A
Kohutek
Zachary A
ZA
Redpath
Gerard T
GT
Zhao
Yunge
Y
Wang
Jiahu
J
Shaffrey
Mark E
ME
Hussaini
Isa M
IM
D000818:Animals; D001254:Astrocytoma / Q000473:pathology* / Q000628:therapy; D045744:Cell Line, Tumor; D002465:Cell Movement; D006801:Humans; D047468:Immunoprecipitation; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000502:physiology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000502:physiology*
D026503:Low Density Lipoprotein Receptor-Related Protein-1; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051571:Protein Kinase C-alpha; D014568:Urokinase-Type Plasminogen Activator; D013755:Tetradecanoylphorbol Acetate