G₁ cell cycle progression and the expression of G₁ cyclins are regulated by PI3K/AKT/mTOR/p70S6K1 signaling in human ovarian cancer cells

Abstract

. Expression of CDK6 and ␤-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. phosphatidylinositol 3-kinase; cyclin-dependent kinases; retinoblastoma protein OVARIAN CANCER IS THE LEADING cause of death from gynecological malignancy and the fourth most common cause of cancer death among American women (40). Recent observations indicate that the gene encoding the p110␣ catalytic subunit of phosphatidylinositol 3-kinase (PI3K) is increased in copy number in ϳ40% of primary ovarian cancer cells and several ovarian epithelial carcinoma cell lines. The PI3K inhibitor LY-294002 has been shown to inhibit growth of an ovarian cancer cell line in vitro (48). PI3K is a heterodimeric enzyme composed of 110-kDa catalytic and 85-kDa regulatory subunits (3). PI3K phosphorylates the D3 hydroxyl of phosphoinositides and produces phosphatidylinositol-3-phosphate. PI3K

AKT Pathway is Activated by 1,25-Dihydroxyvitamin D3 and Participates in its Anti-Apoptotic Effect and Cell Cycle Control in Differentiating HL60 Cells

“…15 This so-called "proliferative phase" of monocytic differentiation is also characterized by increased levels of P-ERK 1/2, and ends when p27Kip1 levels increase sufficiently to inhibit the activity of Cdk5. 15 Phosphorylation of p70S6K is generally considered to promote G 1 phase traverse 44 yet it was found to take place during 1,25D-induced differentiation of HL60 cells (Fig. 2B), and was previously reported to be robustly increased during granulocytic differentiation of myeloid leukemic cells.…”

Antiproliferative activity of sulforaphane in Akt-overexpressing ovarian cancer cells

“…Expression of PTEN in ovarian cancer cells suppresses tumor growth (25,26) and its deletion in the mouse ovarian surface epithelium leads to preneoplastic ovarian lesions (27), indicating a strong role for this protein in ovarian cancer etiology. There is ample evidence for the role of the overactivated prosurvival PI3K/Akt pathway in ovarian cancer carcinogenesis (14,15). There is only one study on the effect of sulforaphane on the Akt pathway, which suggests an induction of the pathway in CaCo-2 cells (28).…”

“…Deregulation of the Akt pathway has been observed in many cancer types, including breast, endometrial, thyroid cancers, and melanoma (12,13). Components of the PI3K/Akt pathway are frequently overexpressed in ovarian cancer (14,15) and are thought to play major roles in ovarian cancer carcinogenesis. The overexpression of the Akt pathway is frequently associated with poor prognosis and more aggressive phenotype (16).…”

Ontogeny of phosphoinositide 3-kinase signaling in developing heart: effect of acute β-adrenergic stimulation

“…Levels and activities of the PI3K signaling and positive regulators of the cell cycle are significantly downregulated in adult heart, which coincides with the loss of proliferative capacity in cardiomyocytes. Furthermore, inhibition of PI3K has been shown to induce G 1 cell cycle arrest and to inhibit cell proliferation via involvement of cyclin D1, CDK, and CDC25A (24). Hence, the shift of cardiomyocyte growth from hyperplasia to hypertrophy may involve, among other factors, both the PI3K signaling pathway and cell cycle regulators such as cyclin, CDK, and CDKI.…”