Top

Journal of Experimental & Clinical Cancer Research

Published in:

Open Access 01-12-2010 | Research

Phosphatidylinositol 3-kinase inhibitor(LY294002) induces apoptosis of human nasopharyngeal carcinoma in vitro and in vivo

Authors: Hanguo Jiang, Desheng Fan, Gengyin Zhou, Xiaofang Li, Huihua Deng

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2010

Abstract

Background

To evaluate whether PI3K/Akt pathway could effect on apoptosis and its mechanism in nasopharyngeal carcinoma cells.

Methods

The activation of the PI3K/Akt and its effect on CNE-2Z cells in vivo and in vitro was investigated by MTT assay, flow cytometry, western blot, ELISA, terminal deoxyribonucleotide transferase-mediated nick-end labeling assays (TUNEL), and immunohistochemical analyses, using PI3K inhibitor, LY294002.

Results

The results showed that LY294002 inhibited the phosphorylating of Akt (S473), cell proliferation, and induced apoptosis in CNE-2Z cells. However, our experiment results also demonstrated that apoptosis-induced LY294002 was directly regulated by caspase-9 activation pathway.

Conclusion

These data suggested that PI3K inhibitor, LY294002, induced apoptosis by caspase-9 activation pathway and might be as a potentially useful target for therapeutic intervention in nasopharyngeal carcinoma patients.

Available only for authorised users

Franke TF, Kaplan DR, Cantley LC: PI3K/AKTion blocks apoptosis (review). Cell. 1997, 88: 435-437. 10.1016/S0092-8674(00)81883-8.CrossRef

Nicholoson KM, Anderson NG: The protein kinaseB/Akt signaling pathway in human malignancy. Cell Signal. 2002, 14: 381-395. 10.1016/S0898-6568(01)00271-6.CrossRef

Hanada M, Feng J, Hemmings BA: Structure, regulation and function of PKB/AKT-a major therapeutic target. Biochim Biophys Acta. 2004, 1693: 3-16.CrossRef

Datta SR, Brunet A, Greenberg ME: Cellular survival: a play in three Akts. Genes Dev. 1999, 13: 2905-2927. 10.1101/gad.13.22.2905.CrossRef

Oka N, Tanimoto S, Taue R, Nakatsuji H, Kishimoto T, Izaki H, Fukumori T, Takahashi M, Nishitani M, Kanayama HO: Role of phosphatidylinositol 3-kinase/Akt pathway in bladder cancer cell apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand. Cancer. 2006, 97: 1093-1098. 10.1111/j.1349-7006.2006.00294.x.

Davies MA, Koul D, Dhesi H, Berman R, McDonnell TJ, McConkey D, Yung WK, Steck PA: Regulation of Akt/PKB activity, cellular growth, and apoptosis in prostate carcinoma cells by MMAC/PTEN. Cancer Res. 1999, 59: 2551-2556.

Liu JL, Sheng X, Hortobagyi ZK, Mao Z, Gallick GE, Yung WK: Nuclear PTEN-mediated growth suppression is independent of Akt down-regulation. Mol Cell Biol. 2005, 25: 6211-6224. 10.1128/MCB.25.14.6211-6224.2005.CrossRef

Grille SJ, Bellacosa A, Upson J, Klein-Szanto AJ, van Roy F, Lee-Kwon W, Donowitz M, Tsichlis PN, Larue L: The protein kinase Akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines. Cancer Res. 2003, 63: 196-206.

Kobayashi I, Semba S, Matsuda Y, Kuroda Y, Yokozaki H: Significance of Akt phosphorylation on tumor growth and vascular endothelial growth factor expression in human gastric carcinoma. Pathobiology. 2006, 73: 8-17. 10.1159/000093087.CrossRef

10.

Sourbier C, Lindner V, Lang H, Agouni A, Schordan E, Danilin S, Rothhut S, Jacqmin D, Helwig JJ, Massfelder T: The phosphoinositide 3-kinase/Akt pathway: A new target in human renal cell carcinoma therapy. Cancer Res. 2006, 66: 5130-5142. 10.1158/0008-5472.CAN-05-1469.CrossRef

11.

Parsons P: Phosphatidylinositol 3-kinase inhibitors are a triple threat to ovarian cancer. Clin Cancer Res. 2005, 11: 7965-7966. 10.1158/1078-0432.CCR-05-1681.CrossRef

12.

Chadrick E, Denlinger MD, Brian K: Inhibition of phosphatidylinositol 3-kinase/Akt and histone deacetylase activity induces apoptosis in non-small cell lung cancer in vivo and in vitro. J Thorac Cardiovasc Surg. 2005, 130: 1422-1429. 10.1016/j.jtcvs.2005.06.051.CrossRef

13.

Roche S, Koegal M, Courtneidge SA: The phosphatidylinositol 3-kinase is required for DNA synthesis induced by some, but not all, growth factors. Proc Natl Acad Sci. 1994, 91: 9185-9189. 10.1073/pnas.91.19.9185.CrossRef

14.

Shivakrupa R, Bernstein A, Watring N, Linnekin D: Phosphatidylinositol 3-kinase is required for growth of mast cells expressing the kit catalytic domain mutant. Cancer Res. 2003, 63: 4412-4419.

15.

Bondar VM, Sweeney-Gotsch B, Andreeff M, Mills GB, McConkey DJ: Inhibition of the phosphoinositide 3-kinase/Akt pathway induces apoptosis in pancreatic carcinoma cells in vivo and in vitro. Mol Cancer Ther. 2002, 1: 989-997.

16.

Hu H, Jiang C, Li G, Lü J: PKB/Akt and ERK regulation of caspase-mediated apoptosis by methylseleninic acid in LNCaP prostate cancer cells. Carcinogenesis. 2005, 26: 1374-1381. 10.1093/carcin/bgi094.CrossRef

17.

Schultz RM, Merriman RL, Andis SL, Bonjouklian R, Grindey GB, Rutherford PG, Gallegos A, Massey K, Powis G: In vivo and in vitro antitumor activity of the phosphatidylinositol 3-kinase inhibitor, wortmannin. Anticancer Res. 1995, 15: 1135-1139.

18.

Hu L, Zaloudek C, Mills GB, Gray J, Jaffe RB: In vivo and in vitro ovarian carcinoma growth inhibition by a phosphatidylinositol 3-kinase inhibitor (LY294002). Clin Cancer Res. 2000, 6: 880-886.

19.

Semba S, Itoh N, Ito M, Harada M, Yamakawa M: The in vivo and in vitro effect of LY29 a specific inhibitor of phosphoinositide 3-kinase, in human colon cancer cells. Clin Cancer Res. 4002, 8: 1957-1965.

20.

Lee CM, Fuhrman CB, Planelles V, Peltier MR, Gaffney DK, Soisson AP, Dodson MK, Tolley HD, Green CL, Zempolich KA: Phosphatidylinositol 3-kinase inhibition by 294002 radiosensitizes in human cervical cell lines. Clin Cancer Res. 2006, 12: 250-256. 10.1158/1078-0432.CCR-05-1084.CrossRef

21.

Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, Reed JC: Regulation of cell death protease caspase-9 by phosphorylation. Science (Wash. DC). 1998, 282: 1318-1321. 10.1126/science.282.5392.1318.CrossRef

22.

Bedogni B, Neill MS, Welony SM, Bouley DM, Giaccia AJ, Denko NC, Powell MB: Topical treatment with inhibitors of the phosphatidylinositol 3-kinase/Akt and Raf/mtogen-activted protein kinase kinase/extracellular signal-regulated kinase pathways reduces melanoma development in severe combined immunodeficient mice. Cancer Res. 2004, 64: 2552-2560. 10.1158/0008-5472.CAN-03-3327.CrossRef

23.

Leger DY, Liagre B, Beneytout JL: Low dose leflunomide activates PI3K signaling in erythroleukemia cells and reduces apoptosis in pancreatic carcinoma cells in vivo and in vitro. Mol Cancer Ther. 2002, 1: 989-997.

24.

Longo PG, Laurenti L, Gobessi S, Sica S, Leone G, Efremov DG: The Akt/Mcl-1 pathway plays a prominent role in mediating antiapoptotic signals downstream of the B-cell receptor in chronic lymphocytic leukemia B cells. Blood. 2008, 111: 846-855. 10.1182/blood-2007-05-089037.CrossRef

25.

Shinohara M, Chung YJ, Saji M, Ringel MD: AKT in thyroid tumorigenesis and progression. Endocrinology. 2007, 148: 942-947. 10.1210/en.2006-0937.CrossRef

26.

Casagrande F, Bacqueville D, Pillaire MJ, Malecaze F, Manenti S, Breton-Douillon M, Darbon JM: G1 phase arrest by the phosphatidylinositol 3-kinase inhibitor LY 294002 is correlated to up-regulation of p27Kip1 and inhibition of G1 CDKs in choroidal melanoma cells. FEBS Lett. 1998, 422: 385-390. 10.1016/S0014-5793(98)00043-X.CrossRef

27.

Weng LP, Brown JL, Eng C: PTEN induces apoptosis and cell cycle arrest through phosphatidylinositol 3-kinase/Akt-dependent and -in dependent pathways. Hum Mol Genet. 2001, 10: 237-242. 10.1093/hmg/10.3.237.CrossRef

28.

Zhou HL, Li XM, Meinkoth J, Pittman RN: Akt regulates cell survival and apoptosis at a postmitochondrial level. J Cell Biol. 2000, 151: 483-494. 10.1083/jcb.151.3.483.CrossRef

Title: Phosphatidylinositol 3-kinase inhibitor(LY294002) induces apoptosis of human nasopharyngeal carcinoma in vitro and in vivo
Authors: Hanguo Jiang
Desheng Fan
Gengyin Zhou
Xiaofang Li
Huihua Deng
Publication date: 01-12-2010
Publisher: BioMed Central
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2010
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/1756-9966-29-34

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2010

Expression of transcription factors snail, slug, and twist in human bladder carcinoma

Expression of MDR1, HIF-1α and MRP1 in sacral chordoma and chordoma cell line CM-319

Identification of sequence polymorphism in the D-Loop region of mitochondrial DNA as a risk factor for hepatocellular carcinoma with distinct etiology

Klotho inhibits growth and promotes apoptosis in human lung cancer cell line A549

CIP2A expression is increased in prostate cancer

Downregulation of SPARC expression decreases gastric cancer cellular invasion and survival

Keynote webinar | Spotlight on antibody–drug conjugates in cancer