| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Advances in Brief |
Human Genetics Program [Y. M., J. R. T.] and Ovarian Cancer Program [M. S., S. J. W., T. C. H.], Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, and Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19104 [S. W. J.]
The cyclin-dependent kinase inhibitor p21WAF1/CIP1/SDI1 (p21) plays a crucial role in DNA repair, cell differentiation, and apoptosis through regulation of the cell cycle. A2780 human ovarian carcinoma cells, which are sensitive to cisplatin and paclitaxel, express wild-type p53 and exhibit a p53-mediated increase in p21 in response to the chemotherapeutic agents. Here, we demonstrate that phosphatidylinositol 3-kinase (PI3K) and its downstream targets serine/threonine kinases AKT1 and AKT2 (AKT), are required for the full induction of p21 in A2780 cells treated with cisplatin or paclitaxel. Inactivation of the PI3K/AKT signal transduction pathway either by its specific inhibitor LY294002 or by expression of dominant negative AKT inhibited p21 expression but had no inhibitory effect on the expression of the proapoptotic protein BAX by cisplatin and paclitaxel treatment. In addition, overexpression of wild-type or constitutively active AKT in A2780 cells sustained the regulation of p21 induction or increased the level of p21 expression, respectively. Experiments with additional ovarian carcinoma cell lines revealed that PI3K is involved in the expression of p21 induced by cisplatin or paclitaxel in OVCAR-10 cells, which have wild-type p53, but not in OVCAR-5 cells, which lack functional p53. These data indicate that the PI3K/AKT signal transduction pathway mediates p21 expression and suggest that this pathway contributes to cell cycle regulation promoted by p53 in response to drug-induced stress. However, inactivation of PI3K/AKT signaling did not result in significant alteration of the drug sensitivity of A2780 cells, suggesting that the cell death induced by cisplatin or paclitaxel proceeds independently of cell protective effects of PI3K and AKT.
This article has been cited by other articles:
|
|
 |
|
  F. R M Latini, J. P Hemerly, G. Oler, G. J Riggins, and J. M Cerutti Re-expression of ABI3-binding protein suppresses thyroid tumor growth by promoting senescence and inhibiting invasion Endocr. Relat. Cancer, September 1, 2008; 15(3): 787 - 799. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Mabuchi, D. A. Altomare, M. Cheung, L. Zhang, P. I. Poulikakos, H. H. Hensley, R. J. Schilder, R. F. Ozols, and J. R. Testa RAD001 Inhibits Human Ovarian Cancer Cell Proliferation, Enhances Cisplatin-Induced Apoptosis, and Prolongs Survival in an Ovarian Cancer Model Clin. Cancer Res., July 15, 2007; 13(14): 4261 - 4270. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L.-Z. Liu, X.-D. Zhou, G. Qian, X. Shi, J. Fang, and B.-H. Jiang AKT1 Amplification Regulates Cisplatin Resistance in Human Lung Cancer Cells through the Mammalian Target of Rapamycin/p70S6K1 Pathway Cancer Res., July 1, 2007; 67(13): 6325 - 6332. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-S. Kim, C. Lee, C. L. Bonifant, H. Ressom, and T. Waldman Activation of p53-Dependent Growth Suppression in Human Cells by Mutations in PTEN or PIK3CA Mol. Cell. Biol., January 15, 2007; 27(2): 662 - 677. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Luo, A. R. Shoemaker, X. Liu, K. W. Woods, S. A. Thomas, R. de Jong, E. K. Han, T. Li, V. S. Stoll, J. A. Powlas, et al. Potent and selective inhibitors of Akt kinases slow the progress of tumors in vivo Mol. Cancer Ther., June 1, 2005; 4(6): 977 - 986. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. B. Hermiller, A. Raizner, L. Cannon, P. A. Gurbel, M. A. Kutcher, S. C. Wong, M. E. Russell, S. G. Ellis, R. Mehran, G. W. Stone, et al. Outcomes with the polymer-based paclitaxel-eluting TAXUS stent in patients with diabetes mellitus: The TAXUS-IV trial J. Am. Coll. Cardiol., April 19, 2005; 45(8): 1172 - 1179. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. N. Everly Jr., S. Kusano, and N. Raab-Traub Accumulation of Cytoplasmic {beta}-Catenin and Nuclear Glycogen Synthase Kinase 3{beta} in Epstein-Barr Virus-Infected Cells J. Virol., November 1, 2004; 78(21): 11648 - 11655. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Gao, D. C. Flynn, Z. Zhang, X.-S. Zhong, V. Walker, K. J. Liu, X. Shi, and B.-H. Jiang G1 cell cycle progression and the expression of G1 cyclins are regulated by PI3K/AKT/mTOR/p70S6K1 signaling in human ovarian cancer cells Am J Physiol Cell Physiol, August 1, 2004; 287(2): C281 - C291. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. W. Stone, S. G. Ellis, D. A. Cox, J. Hermiller, C. O'Shaughnessy, J. T. Mann, M. Turco, R. Caputo, P. Bergin, J. Greenberg, et al. A Polymer-Based, Paclitaxel-Eluting Stent in Patients with Coronary Artery Disease N. Engl. J. Med., January 15, 2004; 350(3): 221 - 231. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Facchetti, D. Uberti, M. Memo, and C. Missale Nerve Growth Factor Restores p53 Function in Pituitary Tumor Cell Lines via trkA-Mediated Activation of Phosphatidylinositol 3-Kinase Mol. Endocrinol., January 1, 2004; 18(1): 162 - 172. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Dupont, M. Karas, and D. LeRoith The Cyclin-dependent Kinase Inhibitor p21CIP/WAF Is a Positive Regulator of Insulin-like Growth Factor I-induced Cell Proliferation in MCF-7 Human Breast Cancer Cells J. Biol. Chem., September 26, 2003; 278(39): 37256 - 37264. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. C. Holsinger, D. D. Doan, S. A. Jasser, E. A. Swan, J. S. Greenberg, B. A. Schiff, B. N. Bekele, M. N. Younes, C. D. Bucana, I. J. Fidler, et al. Epidermal Growth Factor Receptor Blockade Potentiates Apoptosis Mediated by Paclitaxel and Leads to Prolonged Survival in a Murine Model of Oral Cancer Clin. Cancer Res., August 1, 2003; 9(8): 3183 - 3189. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Selvakumaran, D. A. Pisarcik, R. Bao, A. T. Yeung, and T. C. Hamilton Enhanced Cisplatin Cytotoxicity by Disturbing the Nucleotide Excision Repair Pathway in Ovarian Cancer Cell Lines Cancer Res., March 15, 2003; 63(6): 1311 - 1316. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-L. Yang, J.-X. Pan, L. Sun, and S.-C. J. Yeung p21 Waf-1 (Cip-1) Enhances Apoptosis Induced by Manumycin and Paclitaxel in Anaplastic Thyroid Cancer Cells J. Clin. Endocrinol. Metab., February 1, 2003; 88(2): 763 - 772. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-L. Merlin, M. Barberi-Heyob, and N. Bachmann In vitro comparative evaluation of trastuzumab (Herceptin(R)) combined with paclitaxel (Taxol(R)) or docetaxel (Taxotere(R)) in HER2-expressing human breast cancer cell lines Ann. Onc., November 1, 2002; 13(11): 1743 - 1748. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. W. Krystal, G. Sulanke, and J. Litz Inhibition of Phosphatidylinositol 3-Kinase-Akt Signaling Blocks Growth, Promotes Apoptosis, and Enhances Sensitivity of Small Cell Lung Cancer Cells to Chemotherapy Mol. Cancer Ther., September 1, 2002; 1(11): 913 - 922. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Mabuchi, M. Ohmichi, A. Kimura, K. Hisamoto, J. Hayakawa, Y. Nishio, K. Adachi, K. Takahashi, E. Arimoto-Ishida, Y. Nakatsuji, et al. Inhibition of Phosphorylation of BAD and Raf-1 by Akt Sensitizes Human Ovarian Cancer Cells to Paclitaxel J. Biol. Chem., August 30, 2002; 277(36): 33490 - 33500. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Watcharasit, G. N. Bijur, J. W. Zmijewski, L. Song, A. Zmijewska, X. Chen, G. V. W. Johnson, and R. S. Jope Direct, activating interaction between glycogen synthase kinase-3beta and p53 after DNA damage PNAS, June 11, 2002; 99(12): 7951 - 7955. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Li, D. Dowbenko, and L. A. Lasky AKT/PKB Phosphorylation of p21Cip/WAF1 Enhances Protein Stability of p21Cip/WAF1 and Promotes Cell Survival J. Biol. Chem., March 22, 2002; 277(13): 11352 - 11361. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Lawlor and D. R. Alessi PKB/Akt: a key mediator of cell proliferation, survival and insulin responses? J. Cell Sci., March 10, 2002; 114(16): 2903 - 2910. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Del Bufalo, V. Di Castro, A. Biroccio, M. Varmi, D. Salani, L. Rosano, D. Trisciuoglio, F. Spinella, and A. Bagnato Endothelin-1 Protects Ovarian Carcinoma Cells against Paclitaxel-Induced Apoptosis: Requirement for Akt Activation Mol. Pharmacol., March 1, 2002; 61(3): 524 - 532. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-i. Okano and A. K. Rustgi Paclitaxel Induces Prolonged Activation of the Ras/MEK/ERK Pathway Independently of Activating the Programmed Cell Death Machinery J. Biol. Chem., May 25, 2001; 276(22): 19555 - 19564. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
