Effects of Eg5 knockdown on human prostate cancer xenograft growth and chemosensitivity.
OBJECTIVE
Microtubular inhibitors, including docetaxel, are active cytotoxics in many cancers, including prostate cancer (CaP). The Eg5 gene, a member of the kinesin-5 family, plays critical roles in proper mitotic spindle function, and is a potential microtubule-related target for proliferating cancer cells. To investigate the functional activities of Eg5 in CaP, we used an antisense oligonucleotide (ASO) targeting Eg5 to assess the potency and anti-cancer activity of Eg5 ASO treatment for androgen-independent CaP cells in vitro and in vivo.


RESULTS
PC3 cells express higher Eg5 protein and mRNA levels compared to LNCaP cells. In both cell lines, Eg5 ASO treatment reduced mRNA and protein levels in a dose-dependent manner and a complete reduction of Eg5 protein levels was observed at 100 nM. Dose-dependent inhibition in cell growth, potent G2/M phase arrest, and increases in apoptotic sub-G1 fraction were also observed using Eg5 ASO. Surprisingly, low dose Eg5 ASO significantly antagonized cytotoxic effects of paclitaxel. In vivo, Eg5 ASO monotherapy significantly reduced both LNCaP and PC-3 tumor growth but combination treatment with paclitaxel did not yield additive benefits.


CONCLUSIONS
These findings suggest that while Eg5 is a potential target to delay androgen-independent CaP growth, combination treatment with paclitaxel may not be desirable.
The Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada.
Norihiro
N
Hayashi
Erich
E
Koller
Ladan
L
Fazli
Martin E
ME
Gleave
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D004359:Drug Therapy, Combination; D006801:Humans; D016547:Kinesins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009841:Oligonucleotides / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology* / Q000627:therapeutic use; D017239:Paclitaxel / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; C531358:ISIS 183891; C470243:KIF11 protein, human; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D050257:Tubulin Modulators; D016547:Kinesins; D017239:Paclitaxel