Protein kinase c-a-mediated regulation of low-density lipoprotein receptor-related protein and urokinase increases astrocytoma invasion

被引:38
作者
Amos, Samson [1 ]
Mut, Melike
diPierro, Charles G.
Carpenter, Joan E.
Xiao, Aizhen
Kohutek, Zachary A.
Redpath, Gerard T.
Zhao, Yunge
Wang, Jiahu
Shaffrey, Mark E.
Hussaini, Isa M.
机构
[1] Univ Virginia Hlth Syst, Dept Pathol, Charlottesville, VA 22908 USA
[2] Univ Virginia Hlth Syst, Dept Neurosci, Charlottesville, VA 22908 USA
[3] Univ Virginia Hlth Syst, Dept Neurol Surg, Charlottesville, VA 22908 USA
[4] Univ Virginia Hlth Syst, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22908 USA
[5] Ottawa Hlth Res Inst, Ctr Canc Therapeut, Ottawa, ON, Canada
关键词
D O I
10.1158/0008-5472.CAN-07-0030
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:10241 / 10251
页数:11
相关论文
共 49 条
[1]   PKC-η mediates glioblastoma cell proliferation through the Akt and mTOR signaling pathways [J].
Aeder, SE ;
Martin, PM ;
Soh, JW ;
Hussaini, IM .
ONCOGENE, 2004, 23 (56) :9062-9069
[2]   Phorbol 12-myristate 13-acetate induces epidermal growth factor receptor transactivation via protein kinase Cδ/c-Src pathways in glioblastoma cells [J].
Amos, S ;
Martin, PM ;
Polar, GA ;
Parsons, SJ ;
Hussaini, IM .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (09) :7729-7738
[3]  
Basu A, 1996, CELL GROWTH DIFFER, V7, P1507
[4]   LRP: Role in vascular wall integrity and protection from atherosclerosis [J].
Boucher, P ;
Gotthardt, M ;
Li, WP ;
Anderson, RGW ;
Herz, J .
SCIENCE, 2003, 300 (5617) :329-332
[5]   Low density lipoprotein receptor-related protein is expressed early and becomes restricted to a somatodendritic domain during neuronal differentiation in culture [J].
Brown, MD ;
Banker, GA ;
Hussaini, IM ;
Gonias, SL ;
VandenBerg, SR .
BRAIN RESEARCH, 1997, 747 (02) :313-317
[6]  
BU GJ, 1994, J BIOL CHEM, V269, P29874
[7]   The role of protein kinase Cα in U-87 glioma invasion [J].
Cho, KK ;
Mikkelsen, T ;
Lee, YJ ;
Jiang, F ;
Chopp, M ;
Rosenblum, ML .
INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE, 1999, 17 (5-6) :447-461
[8]   ENHANCED PROTEIN-KINASE-C ACTIVITY CORRELATES WITH THE GROWTH-RATE OF MALIGNANT GLIOMAS INVITRO [J].
COULDWELL, WT ;
UHM, JH ;
ANTEL, JP ;
YONG, VW .
NEUROSURGERY, 1991, 29 (06) :880-887
[9]   Targeting protein kinase C: New therapeutic opportunities against high-grade malignant gliomas? [J].
da Rocha, AB ;
Mans, DRA ;
Regner, A ;
Schwartsmann, G .
ONCOLOGIST, 2002, 7 (01) :17-33
[10]   Specificity and mechanism of action of some commonly used protein kinase inhibitors [J].
Davies, SP ;
Reddy, H ;
Caivano, M ;
Cohen, P .
BIOCHEMICAL JOURNAL, 2000, 351 (351) :95-105