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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2009, Vol. 3 Issue (3) : 341-346    https://doi.org/10.1007/s11684-009-0067-9
Research articles
Effects of phosphatidylinositol 3-kinase inhibitor on human cervical carcinoma cells
Yuan ZHANG MD , Xiaoyan ZHANG MM , Yanhui LI MM , Xuan DU MM , Zehua WANG MD, PhD , Hongbo WANG MD ,
Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China;
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Abstract Phosphatidylinositol 3-kinase (PI3K) is a crucial cell survival pathway implicated in tumorigenesis because of its role in stimulating cell proliferation and suppressing apoptosis. This study was to investigate the regulation of proliferation and apoptosis by LY294002, an inhibitor of PI3K in cervical cancer cells and the expression of FLICE-like inhibitory protein (c-FLIP) in vitro. Human cervical cancer HeLa cells were used in this experiment and cultured. The cultured cells were treated with LY294002 at different concentrations (10, 25, 50 and 100µmol/L) for 6, 12, 24, and 48h before harvesting for evaluation. Cell viability was measured by 3-(4,5)-dimethylthiazol(-2-y1)-3,5-di-phenyltetrazoliumbromide (MTT) assay. Apoptosis was analyzed by flow cytometry. The expression of c-FLIP was detected by Western blot. Cell viability was inhibited by LY294002 significantly (P<0.05). Flow cytometry analysis revealed that cell apoptosis was significantly increased in the presence of LY294002 as compared with the control group. Although the expression of c-FLIP was increased in a short time, the expression of c-FLIP was markedly suppressed after the treatment of LY294002 for 48h. These results suggested that the PI3K/Akt signal pathway might be involved in the regulation of cell apoptosis in cervical cancer cells. Moreover, the regulation of c-FLIP expression through PI3K/Akt signal pathway in cervical cancer cells was observed in vitro.
Keywords human cervical cancer cells      apoptosis      phosphatidylinositol 3-kinase (PI3K)/Akt      FLICE-like inhibitory protein      
Issue Date: 05 September 2009
 Cite this article:   
Zehua WANG MD,Yuan ZHANG MD,Yanhui LI MM, et al. Effects of phosphatidylinositol 3-kinase inhibitor on human cervical carcinoma cells [J]. Front. Med., 2009, 3(3): 341-346.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-009-0067-9
https://academic.hep.com.cn/fmd/EN/Y2009/V3/I3/341
Ma B B Y, Bristow R G, Kim J, Siu L L. Combined-modalitytreatment of solid tumors using radiotherapy and molecular targetedagents. J Clin Oncol, 2003, 21(14): 2760―2776

doi: 10.1200/JCO.2003.10.044
Ullrich A, Schlessinger J. Signal transduction by receptorswith tyrosine kinase activity. Cell, 1990, 61(2): 203―212

doi: 10.1016/0092-8674(90)90801-K
Blackhall F H, Pintilie M, Michael M, Leighl N, Feld R, Tsao M S, Shepherd R A. Expression and prognostic significance of kit, protein kinase B,and mitogen-activated protein kinase in patients with small cell lungcancer. Clin Cancer Res, 2003, 9(6): 2241―2247
Fresno Vara J A, Casado E, de Castro J, Cejas P, Belda-Iniesta C, Gonzalez-Baron M. PI3K/Akt signaling pathway and cancer. Cancer Treat Rev, 2004, 30(2): 193―204

doi: 10.1016/j.ctrv.2003.07.007
Toker A, Cantley L C. Signaling through the lipidproducts of phosphoinositide-3-OH kinase. Nature, 1997, 387(6634): 673―676

doi: 10.1038/42648
Yuan Z Q, Sun M, Feldman R I, Wang G, Ma X L, Jiang C, Coppola D, Nicosia S V, Cheng J Q. Frequentactivation of AKT2 and induction of apoptosis by inhibition of phosphoinositide-3-OHkinase/Akt pathway in human ovarian cancer. Oncogene, 2000, 19(19): 2324―2330

doi: 10.1038/sj.onc.1203598
Choe G, Horvath S, Cloughesy T F, Crosby K, Seligson D, Palotie A, Inge L, Smith B L, Sawyers C L, Mischel P S. Analysis of the phosphatidylinositol3'-kinase signaling pathway in glioblastoma patients in vivo. Cancer Res, 2003, 63(11): 2742―2746
Harris C P, Lu X Y, Narayan G, Singh B, Murty V V, Rao P H. Comprehensive molecular cytogenetic characterization of cervicalcancer cell lines. Genes Chromosomes Cancer, 2003, 36(3): 233―241

doi: 10.1002/gcc.10158
Ma Y Y, Wei S J, Lin Y C, Lung J C, Chang T C, Whang-Peng J, Liu J M, Yang D M, Yang W K, Shen C Y. PI3KCA as an oncogene in cervical cancer. Oncogene, 2000, 19(28): 2739―2744

doi: 10.1038/sj.onc.1203597
Blagosklonny M V. Prospective strategies to enforce selectively cell death in cancercells. Oncogene, 2004, 23(16): 2967―2975

doi: 10.1038/sj.onc.1207520
Wetzker R, Rommel C. Phosphoinositide 3-kinasesas targets for therapeutic intervention. Curr Pharm Des, 2004, 10(16): 1915―1922

doi: 10.2174/1381612043384402
Kawaguchi W, Itamochi H, Kigawa J, Kanamori Y, Oishi T, Shimada M, Sato S, Shimogai R, Sato S, Terakawa N. Simultaneous inhibition ofthe mitogen-activated protein kinase and phosphatidylinositol 3'-kinasepathways enhances sensitivity to paclitaxel in ovarian carcinoma. Cancer Sci, 2007, 98(12): 2002―2008

doi: 10.1111/j.1349-7006.2007.00624.x
Houston A, O'Connell J. The Fas signaling pathwayand its role in the pathogenesis of cancer. Curr Opin Pharmacol, 2004, 4(4): 321―326

doi: 10.1016/j.coph.2004.03.008
Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V, Bodmer J L, Schröter M, Burns K, Mattmann C, Rimoldi D, French L E, Tschopp J. Inhibitionof death receptor signals by cellular FLIP. Nature, 1997, 388(6638): 190―195

doi: 10.1038/40657
Krueger A, Baumann S, Krammer P H, Kirchhoff S, FLICE-inhibitoryproteins: regulators of death receptor-mediated apoptosis. Mol Cell Biol, 2001, 21(24): 8247―8254

doi: 10.1128/MCB.21.24.8247-8254.2001
Mathas S, Lietz A, Anagnostopoulos I, Hummel F, Wiesner B, Janz M, Jundt F, Hirsch B, Jöhrens-Leder K, Vornlocher HP, Bommert K, Stein H, Dörken B. c-FLIP mediates resistanceof Hodgkin/Reed-Sternberg cells to death receptor-induced apoptosis. J Exp Med, 2004, 199(8): 1041―1052

doi: 10.1084/jem.20031080
Panka D J, Mano T, Suhara T, Walsh K, Mier J W. Phosohatidylinositol 3-kinse/Akt activityregulates c-FLIP expression in tumor cells. J Biol Chem, 2001, 276(10): 6893―6896

doi: 10.1074/jbc.C000569200
Roymans D, Slegers H. Phosphatidylinositol 3-kinasesin tumor progression. Eur J Biochem, 2001, 268(3): 487―498

doi: 10.1046/j.1432-1327.2001.01936.x
Kim S H, Juhnn Y S, Kang S. Human papillomavirus 16 E5 up-regulates the expressionof vascular endothelial growth factor through the activation of epidermalgrowth factor receptor, MEK/ERK1, 2 and PI3K/Akt. Cell Mol Life Sci, 2006, 63(7,8): 930―938
Zhang X Y, Zhang H Y, Zhang P N, Lu X, Sun H. Elevated phosphatidylinositol 3-kinaseactivation and its clinicopathological significance in cervical cancer. Eur J Obstet Gynecol Reprod Biol, 2008, 139(2): 237―244

doi: 10.1016/j.ejogrb.2007.12.021
Krystal G W, Sulanke G, Litz J. Inhibition of phosphatidylinositol 3-kinase-Akt signalingblocks growth, promotes apoptosis, and enhances sensitivity of smallcell lung cancer cells to chemotherapy. Mol Cancer Ther, 2002, 1(11): 913―922
Xu Q, Simpson S E, Scialla T J, Bagg A, Carroll M. Survival of acute myeloid leukemia cellsrequires PI3 kinase activation. Blood, 2003,102(3): 972―980

doi: 10.1182/blood-2002-11-3429
Lee C M, Fuhrman C B, Planelles V, Tolley H D, Green C L, Zempolich K A. Phosphatidylinositol 3-kinase inhibition by LY294002radiosensitizes human cervical cancer cell lines. Clin Cancer Res, 2006, 12(1): 250―256

doi: 10.1158/1078-0432.CCR-05-1084
Fuhrman C B, Kilgore J, LaCoursiere Y D, Lee C M, Milash B A, Soisson A P, Zempolich KA.Radiosensitization of cervical cancer cells via double-strand DNAbreak repair inhibition. Gynecol Oncol, 2008, 110(1): 93―98

doi: 10.1016/j.ygyno.2007.08.073
Kang Y C, Kim K M, Lee K S. Serum bioactive lysophospholipids prevent TRAIL-inducedapoptosis via PI3K/Akt-dependent cFLIP expression and Bad phosphorylation. Cell Death Differ, 2004, 11(12): 1287―1298

doi: 10.1038/sj.cdd.4401489
Davies C C, Mason J, Wakelam M J, Young L S, Eliopoulos A G. Inhibition of phosphatidylinositol3-kinase- and ERK MAPK-regulated protein synthesis reveals the pro-apoptoticproperties of CD40 ligation in carcinoma cells. J Biol Chem, 2004, 279(2): 1010―1019

doi: 10.1074/jbc.M303820200
Martelli A M, Tazzari P L, Tabellini G. A new selective AKT pharmacological inhibitor reducesresistance to chemotherapeutic drugs, TRAIL, all-trans-retinoic acid,and ionizing radiation of human leukemia cells. Leukemia, 2003, 17(9): 1794―1805

doi: 10.1038/sj.leu.2403044
Kondo G, Iwase M, Watanabe H, Uchida M, Takaoka S, Ohashi M, Nagumo M. Enhancementof susceptibility to Fas-mediated apoptosis in oral squamous cellcarcinoma cells by phosphatidylinositol 3-kinase inhibitor. Oral Oncol, 2006, 42(7): 745―752

doi: 10.1016/j.oraloncology.2005.11.015
Moriyama H, Yonehara S. Rapid up-regulation of c-FLIPexpression by BCR signaling through the PI3K/Akt pathway inhibitssimultaneously induced Fas-mediated apoptosis in murine B lymphocytes. Immunol Lett, 2007, 15, 109(1): 36―46
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