Pleiotrophin signaling through anaplastic lymphoma kinase is rate-limiting for glioblastoma growth.
Glioblastoma multiforme is the most common highly aggressive human brain cancer, and receptor tyrosine kinases have been implicated in the progression of this malignancy. We have recently identified anaplastic lymphoma kinase (ALK) as a tyrosine kinase receptor for pleiotrophin, a secreted growth factor that is highly expressed during embryonic brain development and in tumors of the central nervous system. Here we report on the contribution of pleiotrophin-ALK signaling to glioblastoma growth. We found ALK overexpressed in human glioblastoma relative to normal brain and detected ALK mRNA in glioblastoma cell lines. We reduced the endogenous ALK in glioblastoma cells by ribozyme targeting and demonstrated that this prevents pleiotrophin-stimulated phosphorylation of the anti-apoptotic protein Akt. Furthermore, this depletion of ALK reduced tumor growth of xenografts in athymic nude mice and prolonged survival of the animals because of increased apoptosis in the tumors. These findings directly implicate ALK signaling as a rate-limiting factor in the growth of glioblastoma multiforme and suggest potential utility of therapeutic targeting of ALK.
Powers
Ciaran
C
Lombardi Cancer Center, Department of Oncology, Georgetown University, Washington, DC, 20007, USA.
Aigner
Achim
A
Stoica
Gerald E
GE
McDonnell
Kevin
K
Wellstein
Anton
A
D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001921:Brain / Q000196:embryology; D001932:Brain Neoplasms / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002455:Cell Division; D016207:Cytokines / Q000378:metabolism*; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D007700:Kinetics; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D016337:RNA, Catalytic / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases; D012260:Ribonucleases / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D016207:Cytokines; D016337:RNA, Catalytic; D012333:RNA, Messenger; C066845:pleiotrophin; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D012260:Ribonucleases