Targeting stathmin in prostate cancer.
Stathmin is the founding member of a family of microtubule-destabilizing proteins that regulate the dynamics of microtubule polymerization and depolymerization. Stathmin is expressed at high levels in a variety of human cancers and provides an attractive molecule to target in cancer therapies that disrupt the mitotic apparatus. We developed replication-deficient bicistronic adenoviral vectors that coexpress green fluorescent protein and ribozymes that target stathmin mRNA. The therapeutic potential of these recombinant adenoviruses was tested in an experimental androgen-independent LNCaP prostate cancer model. Adenovirus-mediated transfer of anti-stathmin ribozymes resulted in efficient transduction and marked inhibition of stathmin expression in these cells. Cells that were transduced with the anti-stathmin adenoviruses showed a dramatic dose-dependent growth inhibition. This was associated with accumulation of LNCaP cells in the G2-M phases of the cell cycle. A similar dose-dependent inhibition of clonogenic potential was also observed in cells infected with anti-stathmin adenoviruses. Morphologic and biochemical analysis of infected cells showed a marked increase in apoptosis characterized by detachment of the cells, increased chromatin condensation, activation of caspase-3, and fragmentation of internucleosomal DNA. If these findings are confirmed in vivo, it may provide an effective approach for the treatment of prostate cancer.
Mistry
Sucharita J
SJ
Division of Hematology-Oncology, Department of Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA. sucharita.mistry@mssm.edu
Bank
Alexander
A
Atweh
George F
GF
D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology*; D016337:RNA, Catalytic / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics; D011995:Recombination, Genetic; D050777:Stathmin / Q000235:genetics / Q000276:immunology / Q000502:physiology*
D016337:RNA, Catalytic; D012333:RNA, Messenger; D050777:Stathmin