PMID- 22545128
OWN - NLM
STAT- MEDLINE
DCOM- 20120827
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 4
DP  - 2012
TI  - Inhibitors of phosphatidylinositol 3'-kinases promote mitotic cell death in HeLa 
      cells.
PG  - e35665
LID - 10.1371/journal.pone.0035665 [doi]
LID - e35665
AB  - The phosphatidylinositol 3-kinase (PI3K) pathway plays an important role in many 
      biological processes, including cell cycle progression, cell growth, survival, 
      actin rearrangement and migration, and intracellular vesicular transport. 
      However, the involvement of the PI3K pathway in the regulation of mitotic cell 
      death remains unclear. In this study, we treated HeLa cells with the PI3K 
      inhibitors, 3-methyladenine (3-MA, as well as a widely used autophagy inhibitor) 
      and wortmannin to examine their effects on cell fates using live cell imaging. 
      Treatment with 3-MA decreased cell viability in a time- and dose-dependent manner 
      and was associated with caspase-3 activation. Interestingly, 3-MA-induced cell 
      death was not affected by RNA interference-mediated knockdown (KD) of beclin1 (an 
      essential protein for autophagy) in HeLa cells, or by deletion of atg5 (an 
      essential autophagy gene) in mouse embryonic fibroblasts (MEFs). These data 
      indicate that cell death induced by 3-MA occurs independently of its ability to 
      inhibit autophagy. The results from live cell imaging studies showed that the 
      inhibition of PI3Ks increased the occurrence of lagging chromosomes and cell 
      cycle arrest and cell death in prometaphase. Furthermore, PI3K inhibitors 
      promoted nocodazole-induced mitotic cell death and reduced mitotic slippage. 
      Overexpression of Akt (the downstream target of PI3K) antagonized PI3K 
      inhibitor-induced mitotic cell death and promoted nocodazole-induced mitotic 
      slippage. These results suggest a novel role for the PI3K pathway in regulating 
      mitotic progression and preventing mitotic cell death and provide justification 
      for the use of PI3K inhibitors in combination with anti-mitotic drugs to combat 
      cancer.
FAU - Hou, Heli
AU  - Hou H
AD  - School of Life Sciences, University of Science and Technology of China, Hefei, 
      China.
FAU - Zhang, Yingyin
AU  - Zhang Y
FAU - Huang, Yun
AU  - Huang Y
FAU - Yi, Qiyi
AU  - Yi Q
FAU - Lv, Lei
AU  - Lv L
FAU - Zhang, Tianwei
AU  - Zhang T
FAU - Chen, Dawei
AU  - Chen D
FAU - Hao, Qiaomei
AU  - Hao Q
FAU - Shi, Qinghua
AU  - Shi Q
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120424
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Androstadienes)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 5142-23-4 (3-methyladenine)
RN  - EC 3.4.22.- (Caspase 3)
RN  - JAC85A2161 (Adenine)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - Adenine/*analogs & derivatives/pharmacology
MH  - Androstadienes/*pharmacology
MH  - Animals
MH  - Caspase 3/metabolism
MH  - Cell Cycle Checkpoints/drug effects
MH  - Cell Death/*drug effects
MH  - Cell Line
MH  - Cell Survival/drug effects
MH  - Fibroblasts/cytology/drug effects/metabolism
MH  - HeLa Cells
MH  - Humans
MH  - Mice
MH  - Neoplasms/drug therapy
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Wortmannin
PMC - PMC3335795
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/05/01 06:00
MHDA- 2012/08/28 06:00
PMCR- 2012/04/24
CRDT- 2012/05/01 06:00
PHST- 2011/11/09 00:00 [received]
PHST- 2012/03/19 00:00 [accepted]
PHST- 2012/05/01 06:00 [entrez]
PHST- 2012/05/01 06:00 [pubmed]
PHST- 2012/08/28 06:00 [medline]
PHST- 2012/04/24 00:00 [pmc-release]
AID - PONE-D-11-22394 [pii]
AID - 10.1371/journal.pone.0035665 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(4):e35665. doi: 10.1371/journal.pone.0035665. Epub 2012 Apr 24.