This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hirose, Y. Articles by Pieper, R. O. Search for Related Content PubMed PubMed Citation Articles by Hirose, Y. Articles by Pieper, R. O.

Akt Activation Suppresses Chk2-Mediated, Methylating Agent–Induced G₂ Arrest and Protects from Temozolomide-Induced Mitotic Catastrophe and Cellular Senescence

Department of Neurological Surgery and the Brain Tumor Research Center, University of California at San Francisco, San Francisco, California

Requests for reprints: Russell O. Pieper, UCSF Comprehensive Cancer Center, Room N261, 2340 Sutter Street, San Francisco, CA 94115-0875. Phone: 415-502-7132; Fax: 415-502-6779; E-mail: rpieper{at}cc.ucsf.edu.

Pharmacologic inhibition of the DNA signal transducers Chk1 and p38 blocks G₂ arrest and sensitizes glioblastoma cells to chemotherapeutic methylating agent–induced cytotoxicity. Because Akt pathway activation has been suggested to also block G₂ arrest induced by DNA-damaging agents and because glioma cells frequently have high levels of Akt activation, we examined the contribution of the Akt pathway to methylating agent–induced G₂ arrest and toxicity. U87MG human glioma cells containing an inducible Akt expression construct were incubated with inducing agent or vehicle, after which the cells were exposed to temozolomide and assayed for activation of the components of the G₂ arrest pathway and survival. Temozolomide-treated control cells activated the DNA damage signal transducers Chk1, Chk2, and p38, leading to Cdc25C and Cdc2 inactivation, prolonged G₂ arrest, and loss of clonagenicity by a combination of senescence and mitotic catastrophe. Temozolomide-treated cells induced to overexpress Akt, however, exhibited significantly less drug-induced Cdc25C/Cdc2 inactivation and less G₂ arrest. Akt-mediated suppression of G₂ arrest was associated not with alterations in Chk1 or p38 activation but rather with suppression of Chk2 activation and reduced recruitment of Chk2 to sites of damage in chromatin. Unlike bypass of the G₂ checkpoint induced by pharmacologic inhibitors of Chk1 or p38, however, Akt-induced bypass of G₂ arrest suppressed, rather than enhanced, temozolomide-induced senescence and mitotic catastrophe. These results show that whereas Akt activation suppresses temozolomide-induced Chk2 activation and G₂ arrest, the overriding effect is protection from temozolomide-induced cytotoxicity. The Akt pathway therefore represents a new target for the sensitization of gliomas to chemotherapeutic methylating agents such as temozolomide.

This article has been cited by other articles:

				J. Lu, J. S. Kovach, F. Johnson, J. Chiang, R. Hodes, R. Lonser, and Z. Zhuang Inhibition of serine/threonine phosphatase PP2A enhances cancer chemotherapy by blocking DNA damage induced defense mechanisms PNAS, July 14, 2009; 106(28): 11697 - 11702. [Abstract] [Full Text] [PDF]

				J. G. Madson, D. T. Lynch, J. Svoboda, R. Ophardt, J. Yanagida, S. K. Putta, A. Bowles, C. S. Trempus, R. W. Tennant, and L. A. Hansen Erbb2 Suppresses DNA Damage-Induced Checkpoint Activation and UV-Induced Mouse Skin Tumorigenesis Am. J. Pathol., June 1, 2009; 174(6): 2357 - 2366. [Abstract] [Full Text] [PDF]

				L. Shen, W.-Y. Au, K.-Y. Wong, N. Shimizu, J. Tsuchiyama, Y.-L. Kwong, R. H. Liang, and G. Srivastava Cell death by bortezomib-induced mitotic catastrophe in natural killer lymphoma cells Mol. Cancer Ther., December 1, 2008; 7(12): 3807 - 3815. [Abstract] [Full Text] [PDF]

				S. Caporali, L. Levati, G. Starace, G. Ragone, E. Bonmassar, E. Alvino, and S. D'Atri AKT Is Activated in an Ataxia-Telangiectasia and Rad3-Related-Dependent Manner in Response to Temozolomide and Confers Protection against Drug-Induced Cell Growth Inhibition Mol. Pharmacol., July 1, 2008; 74(1): 173 - 183. [Abstract] [Full Text] [PDF]

				S.-M. Maira, F. Stauffer, J. Brueggen, P. Furet, C. Schnell, C. Fritsch, S. Brachmann, P. Chene, A. De Pover, K. Schoemaker, et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity Mol. Cancer Ther., July 1, 2008; 7(7): 1851 - 1863. [Abstract] [Full Text] [PDF]

				T. Kimura, M. Tomooka, N. Yamano, K. Murayama, S. Matoba, H. Umehara, Y. Kanai, and T. Nakano AKT signaling promotes derivation of embryonic germ cells from primordial germ cells Development, March 1, 2008; 135(5): 869 - 879. [Abstract] [Full Text] [PDF]

				M. Nagane, K. Kobayashi, A. Ohnishi, S. Shimizu, and Y. Shiokawa Prognostic Significance of O6-Methylguanine-DNA Methyltransferase Protein Expression in Patients with Recurrent Glioblastoma Treated with Temozolomide Jpn. J. Clin. Oncol., December 21, 2007; (2007) hym132v1. [Abstract] [Full Text] [PDF]

				Z. Jiang, N. Pore, G. J. Cerniglia, R. Mick, M.-M. Georgescu, E. J. Bernhard, S. M. Hahn, A. K. Gupta, and A. Maity Phosphatase and Tensin Homologue Deficiency in Glioblastoma Confers Resistance to Radiation and Temozolomide that Is Reversed by the Protease Inhibitor Nelfinavir Cancer Res., May 1, 2007; 67(9): 4467 - 4473. [Abstract] [Full Text] [PDF]

				B. E. Cristiano, J. C. Chan, K. M. Hannan, N. A. Lundie, N. J. Marmy-Conus, I. G. Campbell, W. A. Phillips, M. Robbie, R. D. Hannan, and R. B. Pearson A Specific Role for AKT3 in the Genesis of Ovarian Cancer through Modulation of G2-M Phase Transition Cancer Res., December 15, 2006; 66(24): 11718 - 11725. [Abstract] [Full Text] [PDF]

				P.-L. Kuo, Y.-L. Hsu, and C.-Y. Cho Plumbagin induces G2-M arrest and autophagy by inhibiting the AKT/mammalian target of rapamycin pathway in breast cancer cells Mol. Cancer Ther., December 1, 2006; 5(12): 3209 - 3221. [Abstract] [Full Text] [PDF]

				O. K. Mirzoeva, T. Kawaguchi, and R. O. Pieper The Mre11/Rad50/Nbs1 complex interacts with the mismatch repair system and contributes to temozolomide-induced G2 arrest and cytotoxicity. Mol. Cancer Ther., November 1, 2006; 5(11): 2757 - 2766. [Abstract] [Full Text] [PDF]

				N. Auger, J. Thillet, K. Wanherdrick, A. Idbaih, M.-E. Legrier, B. Dutrillaux, M. Sanson, and M.-F. Poupon Genetic alterations associated with acquired temozolomide resistance in SNB-19, a human glioma cell line. Mol. Cancer Ther., September 1, 2006; 5(9): 2182 - 2192. [Abstract] [Full Text] [PDF]

				C. Billecke, S. Finniss, L. Tahash, C. Miller, T. Mikkelsen, N. P. Farrell, and O. Bogler Polynuclear platinum anticancer drugs are more potent than cisplatin and induce cell cycle arrest in glioma Neuro-oncol, July 1, 2006; 8(3): 215 - 226. [Abstract] [Full Text] [PDF]

				A. Panner, C. D. James, M. S. Berger, and R. O. Pieper mTOR Controls FLIPS Translation and TRAIL Sensitivity in Glioblastoma Multiforme Cells Mol. Cell. Biol., October 15, 2005; 25(20): 8809 - 8823. [Abstract] [Full Text] [PDF]