Skip Navigation



Carcinogenesis Advance Access published online on August 5, 2004
Carcinogenesis, doi:10.1093/carcin/bgh250
© 2004 by Oxford University Press
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrow Supplementary Data
Right arrow All Versions of this Article:
25/12/2397    most recent
bgh250v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Lee, T. K.
Right arrow Articles by Fan, S. T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lee, T. K.
Right arrow Articles by Fan, S. T.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Received March 31, 2004
Revised June 30, 2004
Accepted July 25, 2004

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

FTY720 induces apoptosis of human hepatoma cell lines through PI3-K-mediated Akt dephosphorylation

Terence K. Lee 1, Kwan Man 1*, Joanna W. Ho 1, Chris K. Sun 1, Kevin T. Ng 1, Xiang Hong Wang 2, Yong Chuan Wong 2, Irene O. Ng 3, Ray R. Xu 4, Sheung Tat Fan 1

1 Centre for the Study of Liver Disease, Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong, China
2 Centre for the Study of Liver Disease, Department of Anatomy, The University of Hong Kong, Pokfulam, Hong Kong, China
3 Centre for the Study of Liver Disease, Department of Pathology, The University of Hong Kong, Pokfulam, Hong Kong, China
4 Institute of Molecular Biology, The University of Hong Kong, Pokfulam, Hong Kong, China

* To whom correspondence should be addressed. E-mail: kwanman{at}hkucc.hku.hk.


  Abstract

We aim to study the anticancer effect of the novel immunomodulator FTY720 in vitro and in vivo by investigation of cell cycle entry, cell cycle regulators, cell survival and apoptosis pathways. Three hepatoma cell lines with different p53 status (HepG2, Huh-7 and Hep3B) and one non-tumorigenic immortalized liver cell line (MIHA) were used for in vitro study. In vivo effect of FTY720 was evaluated in a nude mice tumor model. Cell cycle distribution and cell cycle regulator proteins p27 Kip1 and cyclin D1, together with PI3-K/Akt pathway, mitogen-activated protein kinases, and cleaved caspase-3 and 9 were evaluated.

FTY720 selectively induced cell apoptosis in hepatoma cell lines with over-expression of cleaved caspase-3 and 9, but the same phenomenon was not found in MIHA. FTY720 induced Akt dephosphorylation at Ser473 mediated by PI3-K activity inhibition. Its dephosphorylation led to down-regulation of p42/p44, and dephosphorylation of Forkhead transcription factor and GSK-3{beta}, and subsequently up-regulation of p27Kip1 and down-regulation of cyclin D1. In our in vivo model, FTY720 induced apoptosis of tumor cells by down-regulation of Akt pathway. FTY720 suppressed tumor growth without notable side effects in the normal liver. In conclusion, FTY720 is a novel anticancer agent that induces apoptosis of hepatoma cell lines both in vitro and in vivo through PI3-K-mediated Akt dephosphorylation in a p53-independent manner.

Keywords: FTY720; hepatoma; Akt; apoptosis.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
B. Venkatesan, A. J. Valente, V. S. Reddy, D. A. Siwik, and B. Chandrasekar
Resveratrol blocks interleukin-18-EMMPRIN cross-regulation and smooth muscle cell migration
Am J Physiol Heart Circ Physiol, August 1, 2009; 297(2): H874 - H886.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
J.-H. Hung, Y.-S. Lu, Y.-C. Wang, Y.-H. Ma, D.-S. Wang, S. K. Kulp, N. Muthusamy, J. C. Byrd, A.-L. Cheng, and C.-S. Chen
FTY720 Induces Apoptosis in Hepatocellular Carcinoma Cells through Activation of Protein Kinase C {delta} Signaling
Cancer Res., February 15, 2008; 68(4): 1204 - 1212.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
J. W. P. Yam, F. C. F. Ko, C.-Y. Chan, D.-Y. Jin, and I. O.-L. Ng
Interaction of Deleted in Liver Cancer 1 with Tensin2 in Caveolae and Implications in Tumor Suppression.
Cancer Res., September 1, 2006; 66(17): 8367 - 8372.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
A. A. Caro and A. I. Cederbaum
Role of Phosphatidylinositol 3-Kinase/AKT as a Survival Pathway against CYP2E1-Dependent Toxicity
J. Pharmacol. Exp. Ther., July 1, 2006; 318(1): 360 - 372.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
T. K. Lee, K. Man, J. W. Ho, X. H. Wang, R. T.P. Poon, Y. Xu, K. T. Ng, A. C. Chu, C. K. Sun, I. O. Ng, et al.
FTY720: A Promising Agent for Treatment of Metastatic Hepatocellular Carcinoma
Clin. Cancer Res., December 1, 2005; 11(23): 8458 - 8466.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
J. W.Y. Ho, K. Man, C. K. Sun, T. K. Lee, R. T.P. Poon, and S. T. Fan
Effects of a novel immunomodulating agent, FTY720, on tumor growth and angiogenesis in hepatocellular carcinoma
Mol. Cancer Ther., September 1, 2005; 4(9): 1430 - 1438.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
H. Yasui, T. Hideshima, N. Raje, A. M. Roccaro, N. Shiraishi, S. Kumar, M. Hamasaki, K. Ishitsuka, Y.-T. Tai, K. Podar, et al.
FTY720 Induces Apoptosis in Multiple Myeloma Cells and Overcomes Drug Resistance
Cancer Res., August 15, 2005; 65(16): 7478 - 7484.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.