PMID- 15028555
OWN - NLM
STAT- MEDLINE
DCOM- 20040824
LR  - 20220409
IS  - 0363-6143 (Print)
IS  - 0363-6143 (Linking)
VI  - 287
IP  - 2
DP  - 2004 Aug
TI  - G1 cell cycle progression and the expression of G1 cyclins are regulated by 
      PI3K/AKT/mTOR/p70S6K1 signaling in human ovarian cancer cells.
PG  - C281-91
AB  - Ovarian cancer is one of the most common cancers among women. Recent studies 
      demonstrated that the gene encoding the p110alpha catalytic subunit of 
      phosphatidylinositol 3-kinase (PI3K) is frequently amplified in ovarian cancer 
      cells. PI3K is involved in multiple cellular functions, including proliferation, 
      differentiation, antiapoptosis, tumorigenesis, and angiogenesis. In this study, 
      we demonstrate that the inhibition of PI3K activity by LY-294002 inhibited 
      ovarian cancer cell proliferation and induced G(1) cell cycle arrest. This effect 
      was accompanied by the decreased expression of G(1)-associated proteins, 
      including cyclin D1, cyclin-dependent kinase (CDK) 4, CDC25A, and retinoblastoma 
      phosphorylation at Ser(780), Ser(795), and Ser(807/811). Expression of CDK6 and 
      beta-actin was not affected by LY-294002. Expression of the cyclin kinase 
      inhibitor p16(INK4a) was induced by the PI3K inhibitor, whereas steady-state 
      levels of p21(CIP1/WAF1) were decreased in the same experiment. The inhibition of 
      PI3K activity also inhibited the phosphorylation of AKT and p70S6K1, but not 
      extracellular regulated kinase 1/2. The G(1) cell cycle arrest induced by 
      LY-294002 was restored by the expression of active forms of AKT and p70S6K1 in 
      the cells. Our study shows that PI3K transmits a mitogenic signal through AKT and 
      mammalian target of rapamycin (mTOR) to p70S6K1. The mTOR inhibitor rapamycin had 
      similar inhibitory effects on G(1) cell cycle progression and on the expression 
      of cyclin D1, CDK4, CDC25A, and retinoblastoma phosphorylation. These results 
      indicate that PI3K mediates G(1) progression and cyclin expression through 
      activation of an AKT/mTOR/p70S6K1 signaling pathway in the ovarian cancer cells.
FAU - Gao, Ning
AU  - Gao N
AD  - 1820 MBR Cancer Center and Dept. of Microbiology, Immunology and Cell Biology, 
      West Virginia University, Morgantown, WV 26506-9300, USA.
FAU - Flynn, Daniel C
AU  - Flynn DC
FAU - Zhang, Zhuo
AU  - Zhang Z
FAU - Zhong, Xiao-Song
AU  - Zhong XS
FAU - Walker, Valerie
AU  - Walker V
FAU - Liu, Ke Jian
AU  - Liu KJ
FAU - Shi, Xianglin
AU  - Shi X
FAU - Jiang, Bing-Hua
AU  - Jiang BH
LA  - eng
GR  - CA 60731/CA/NCI NIH HHS/United States
GR  - RR 16440/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20040317
PL  - United States
TA  - Am J Physiol Cell Physiol
JT  - American journal of physiology. Cell physiology
JID - 100901225
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Blood Proteins)
RN  - 0 (Chromones)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p16)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Morpholines)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Retinoblastoma Protein)
RN  - 136601-57-5 (Cyclin D1)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (AKT1 protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.22 (CDK4 protein, human)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinase 4)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Antibiotics, Antineoplastic/pharmacology
MH  - Blood Proteins/pharmacology
MH  - Cell Division/physiology
MH  - Chromones/pharmacology
MH  - Cyclin D1/metabolism
MH  - Cyclin-Dependent Kinase 4
MH  - Cyclin-Dependent Kinase Inhibitor p16/metabolism
MH  - Cyclin-Dependent Kinases/metabolism
MH  - Enzyme Inhibitors/pharmacology
MH  - Female
MH  - G1 Phase/drug effects/*physiology
MH  - Humans
MH  - Mitogen-Activated Protein Kinases/metabolism
MH  - Morpholines/pharmacology
MH  - *Ovarian Neoplasms
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation
MH  - Protein Kinase Inhibitors
MH  - Protein Kinases/*metabolism
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - Proto-Oncogene Proteins/*metabolism
MH  - Proto-Oncogene Proteins c-akt
MH  - Retinoblastoma Protein/metabolism
MH  - Ribosomal Protein S6 Kinases, 70-kDa/antagonists & inhibitors/*metabolism
MH  - Signal Transduction/drug effects/*physiology
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Tumor Cells, Cultured
EDAT- 2004/03/19 05:00
MHDA- 2004/08/25 05:00
CRDT- 2004/03/19 05:00
PHST- 2004/03/19 05:00 [pubmed]
PHST- 2004/08/25 05:00 [medline]
PHST- 2004/03/19 05:00 [entrez]
AID - 00422.2003 [pii]
AID - 10.1152/ajpcell.00422.2003 [doi]
PST - ppublish
SO  - Am J Physiol Cell Physiol. 2004 Aug;287(2):C281-91. doi: 
      10.1152/ajpcell.00422.2003. Epub 2004 Mar 17.