Survivin stable knockdown by siRNA inhibits tumor cell growth and angiogenesis in breast and cervical cancers.
Increased resistance to apoptosis is a hallmark of many tumor cells. Survivin, a member of IAP family protein, is expressed in many human cancers and plays an important role in protecting cells from apoptosis. Here we show that vector-based small interfering RNAs (siRNA) stably knockdown survivin expression in several cancer cell lines, leading to increased apoptotic rate in response to different proapoptotic stimuli, such as doxorubicin or TNF-alpha. The apoptotic susceptibility was dependent on divergent levels of survivin expression. The stable transfectants exhibited abnormal morphology, suppressed cell growth, enhanced spontaneous apoptosis and cell cycle hindrance. Furthermore, in nude mice xenografts of survivin-positive tumors, cells expressing survivin-targeted siRNAs exhibited decreased tumor formation and reduced angiogenesis. Results from these studies: (1) provide direct evidence that intracellular silencing of survivin by siRNA sensitizes human tumor cells to apoptosis; (2) define survivin as a promising molecular target for cancer therapy; and (3) suggest the potential applicability of survivin-targeted siRNA for treating human tumors, probably in combination with chemotherapy.
Li
Qing-Xia
QX
State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.
Zhao
Jing
J
Liu
Jia-Yun
JY
Jia
Lin-Tao
LT
Huang
Hong-Yan
HY
Xu
Yan-Ming
YM
Zhang
Yong
Y
Zhang
Rui
R
Wang
Cheng-Ji
CJ
Yao
Li-Bo
LB
Chen
Si-Yi
SY
Yang
An-Gang
AG
D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000098:blood supply / Q000628:therapy*; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000628:therapy*; D034741:RNA, Small Interfering / Q000235:genetics*; D000077022:Survivin; D002583:Uterine Cervical Neoplasms / Q000098:blood supply / Q000628:therapy*; D023041:Xenograft Model Antitumor Assays
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D000077022:Survivin