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G1 cell cycle progression and the expression of G1 cyclins are regulated by PI3K/AKT/mTOR/p70S6K1 signaling in human ovarian cancer cells.
- Source :
-
American journal of physiology. Cell physiology [Am J Physiol Cell Physiol] 2004 Aug; Vol. 287 (2), pp. C281-91. Date of Electronic Publication: 2004 Mar 17. - Publication Year :
- 2004
-
Abstract
- 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.
- Subjects :
- Antibiotics, Antineoplastic pharmacology
Blood Proteins pharmacology
Cell Division physiology
Chromones pharmacology
Cyclin D1 metabolism
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase Inhibitor p16 metabolism
Cyclin-Dependent Kinases metabolism
Enzyme Inhibitors pharmacology
Female
G1 Phase drug effects
Humans
Mitogen-Activated Protein Kinases metabolism
Morpholines pharmacology
Phosphoinositide-3 Kinase Inhibitors
Phosphorylation
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-akt
Retinoblastoma Protein metabolism
Ribosomal Protein S6 Kinases, 70-kDa antagonists & inhibitors
Signal Transduction drug effects
Sirolimus pharmacology
TOR Serine-Threonine Kinases
Tumor Cells, Cultured
G1 Phase physiology
Ovarian Neoplasms
Phosphatidylinositol 3-Kinases metabolism
Protein Kinases metabolism
Protein Serine-Threonine Kinases metabolism
Proto-Oncogene Proteins metabolism
Ribosomal Protein S6 Kinases, 70-kDa metabolism
Signal Transduction physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0363-6143
- Volume :
- 287
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Cell physiology
- Publication Type :
- Academic Journal
- Accession number :
- 15028555
- Full Text :
- https://doi.org/10.1152/ajpcell.00422.2003