G1 Cell Cycle Progression and the Expression of G1 Cyclins Are Regulated by PI3K/AKT/mTOR/p70S6K1 Signaling in Human Ovarian Cancer Cells

Details

• Personal Author:
  Flynn DC ; Gao N ; Jiang BH ; Liu KJ ; Shi X ; Walker V ; Zhang Z ; Zhong XS
• Description:
  Ovarian cancer is one of the most common cancers among women. Recent studies demonstrated that the gene encoding the p110a 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 G1 cell cycle arrest. This effect was accompanied by the decreased expression of G1-associated proteins, including cyclin D1, cyclin-dependent kinase (CDK) 4, CDC25A, and retinoblastoma phosphorylation at Ser780, Ser795, and Ser807/811. Expression of CDK6 and B-actin was not affected by LY-294002. Expression of the cyclin kinase inhibitor p16INK4a was induced by the PI3K inhibitor, whereas steady-state levels of p21CIP1/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 G1 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 G1 cell cycle progression and on the expression of cyclin D1, CDK4, CDC25A, and retinoblastoma phosphorylation. These results indicate that PI3K mediates G1 progression and cyclin expression through activation of an AKT/mTOR/p70S6K1 signaling pathway in the ovarian cancer cells. [Description provided by NIOSH]
• Subjects:
  Carcinogens Cells, Cultured Demography Neoplasms Occupational Health Safety Sex Characteristics
• Keywords:
  Cancer Cell-cultures Cell-differentiation Cell-function Cellular-function Demographic-characteristics Sex-factors Tumorigenesis
• ISSN:
  0363-6143
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  New Mexico ; OSHA Region 3 ; OSHA Region 6 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  287
• Issue:
  2
• NIOSHTIC Number:
  nn:20025980
• Citation:
  Am J Physiol Cell Physiol 2004 Aug; 287(2):C281-C291
• Email:
  bhjiang@hsc.wvu.edu
• Federal Fiscal Year:
  2004
• Peer Reviewed:
  True
• Source Full Name:
  American Journal of Physiology: Cell Physiology
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:f2f3ecbe6cbf1d5307fcac4e6b21d8701b381e19fb1f0fd7c64799f52aec87fda2bd7327a437854521684e667d5889a000174d141a2fa8074e7b80b0b7081b62
• Download URL:
  https://stacks.cdc.gov/view/cdc/197131/cdc_197131_DS1.pdf
• File Type:
  [PDF - 605.27 KB ]