p27Kip1 expression inhibits glioblastoma growth, invasion, and tumor-induced neoangiogenesis.
The tumor suppressor gene CDKN1B encodes for a 27-kDa cyclin-dependent kinase inhibitory protein, p27Kip1, which together with its well-established role in the inhibition of cell proliferation, displays additional activities in the control of gene transcription and cell motility. p27Kip1 thus represents a good candidate for a gene therapy approach, especially in those cancers refractory to the conventional therapies, like human glioblastoma. Here, we show that overexpression of p27Kip1 in glioblastoma cell lines induced cell cycle arrest and inhibition of cell motility through extracellular matrix substrates. The use of adenoviral vectors in the treatment of glioblastoma in vivo showed that p27Kip1 was able to block not only cancer cell growth but also local invasion and tumor-induced neoangiogenesis. The latter effect was due to the ability of p27 to impair both endothelial cell growth and motility, thus preventing proper vessel formation in the tumor. The block of neoangiogenesis depended on cytoplasmic p27Kip1 antimigratory activity and was linked to its ability to bind to and inhibit the microtubule-destabilizing protein stathmin. Our work provides the first evidence that a successful p27Kip1-based gene therapy is linked to tumor microenvironment modification, thus opening new perspectives to the use of gene therapy approaches for the treatment of refractory cancers.
Schiappacassi
Monica
M
Division of Experimental Oncology 2, Centro di Riferimento Oncologico, Istituto Nazionale Tumori, IRCCS, Via Franco Gallini, 2 33081 Aviano, Italy.
Lovat
Francesca
F
Canzonieri
Vincenzo
V
Belletti
Barbara
B
Berton
Stefania
S
Di Stefano
Domenica
D
Vecchione
Andrea
A
Colombatti
Alfonso
A
Baldassarre
Gustavo
G
D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology*; D002465:Cell Movement; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism* / Q000494:pharmacology; D004318:Doxycycline / Q000494:pharmacology; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D005822:Genetic Vectors / Q000378:metabolism; D005909:Glioblastoma / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D050777:Stathmin / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D050777:Stathmin; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004318:Doxycycline