Targeting cyclin B1 inhibits proliferation and sensitizes breast cancer cells to taxol.
BACKGROUND
Cyclin B1, the regulatory subunit of cyclin-dependent kinase 1 (Cdk1), is essential for the transition from G2 phase to mitosis. Cyclin B1 is very often found to be overexpressed in primary breast and cervical cancer cells as well as in cancer cell lines. Its expression is correlated with the malignancy of gynecological cancers.


METHODS
In order to explore cyclin B1 as a potential target for gynecological cancer therapy, we studied the effect of small interfering RNA (siRNA) on different gynecological cancer cell lines by monitoring their proliferation rate, cell cycle profile, protein expression and activity, apoptosis induction and colony formation. Tumor formation in vivo was examined using mouse xenograft models.


RESULTS
Downregulation of cyclin B1 inhibited proliferation of several breast and cervical cancer cell lines including MCF-7, BT-474, SK-BR-3, MDA-MB-231 and HeLa. After combining cyclin B1 siRNA with taxol, we observed an increased apoptotic rate accompanied by an enhanced antiproliferative effect in breast cancer cells. Furthermore, control HeLa cells were progressively growing, whereas the tumor growth of HeLa cells pre-treated with cyclin B1 siRNA was strongly inhibited in nude mice, indicating that cyclin B1 is indispensable for tumor growth in vivo.


CONCLUSIONS
Our data support the notion of cyclin B1 being essential for survival and proliferation of gynecological cancer cells. Concordantly, knockdown of cyclin B1 inhibits proliferation in vitro as well as in vivo. Moreover, targeting cyclin B1 sensitizes breast cancer cells to taxol, suggesting that specific cyclin B1 targeting is an attractive strategy for the combination with conventionally used agents in gynecological cancer therapy.
Androic
Ilija
I
Department of Obstetrics and Gynecology, School of Medicine, J,W, Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
Krämer
Andrea
A
Yan
Ruilan
R
Rödel
Franz
F
Gätje
Regine
R
Kaufmann
Manfred
M
Strebhardt
Klaus
K
Yuan
Juping
J
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019926:Cyclin B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D056744:Cyclin B1; D015536:Down-Regulation; D005260:Female; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017239:Paclitaxel / Q000627:therapeutic use*; D034741:RNA, Small Interfering / Q000627:therapeutic use*; D014162:Transfection / Q000379:methods; D014410:Tumor Stem Cell Assay; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D000972:Antineoplastic Agents, Phytogenic; C534699:CCNB1 protein, human; C534700:Ccnb1 protein, mouse; D019926:Cyclin B; D056744:Cyclin B1; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D017239:Paclitaxel