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Akt/Protein Kinase B Is Constitutively Active in Non-Small Cell Lung Cancer Cells and Promotes Cellular Survival and Resistance to Chemotherapy and Radiation

Developmental Therapeutics Department, Medicine Branch, Division of Clinical Sciences, National Cancer Institute [J. B., A. S. C., Y. N.], and Navy Medical Oncology, National Naval Medical Center [P. A. D.], Bethesda, Maryland 20889

To evaluate the role of Akt/PKB in non-small cell lung cancer (NSCLC) survival, we analyzed NSCLC cell lines that differed in tumor histology as well as p53, Rb, and K-ras status. Constitutive Akt/protein kinase B (PKB) activity was demonstrated in 16 of 17 cell lines by maintenance of S473 phosphorylation with serum deprivation. Additional analysis of five of 2these NSCLC lines revealed that phosphorylation of S473 and T308 correlated with in vitro kinase activity. Akt/PKB activation was phosphatidylinositol 3-kinase-dependent and promoted survival because the phosphatidylinositol 3 inhibitors LY294002 and wortmannin inhibited Akt/PKB phosphorylation, Akt/PKB activity, and increased apoptosis only in cells with active Akt/PKB. To test whether Akt/PKB activity promoted therapeutic resistance, LY294002 was added with individual chemotherapeutic agents or irradiation. LY294002 greatly potentiated chemotherapy-induced apoptosis in cells with high Akt/PKB levels, but did not significantly increase chemotherapy-induced apoptosis in cells with low Akt/PKB levels. Combined with radiation in cells with active Akt/PKB, LY294002 additively increased apoptosis and inhibited clonogenic growth. These results were extended with transiently transfected Akt/PKB mutants. Transfecting dominant negative Akt/PKB decreased Akt/PKB activity and increased basal apoptosis as well as chemotherapy- and irradiation-induced apoptosis only in cells with high Akt/PKB activity. Conversely, transfecting constitutively active Akt/PKB into cells with low Akt/PKB activity increased Akt/PKB activity and attenuated chemotherapy- and radiation-induced apoptosis. We therefore identify Akt/PKB as a constitutively active kinase that promotes survival of NSCLC cells and demonstrate that modulation of Akt/PKB activity by pharmacological or genetic approaches alters the cellular responsiveness to therapeutic modalities typically used to treat patients with NSCLC.

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				Z. Li, J. Jaboin, P. A. Dennis, and C. J. Thiele Genetic and Pharmacologic Identification of Akt as a Mediator of Brain-Derived Neurotrophic Factor/TrkB Rescue of Neuroblastoma Cells from Chemotherapy-Induced Cell Death Cancer Res., March 15, 2005; 65(6): 2070 - 2075. [Abstract] [Full Text] [PDF]

				E. S. Fiala, O. S. Sohn, C.-X. Wang, E. Seibert, J. Tsurutani, P. A. Dennis, K. El-Bayoumy, R. S. Sodum, D. Desai, J. Reinhardt, et al. Induction of preneoplastic lung lesions in guinea pigs by cigarette smoke inhalation and their exacerbation by high dietary levels of vitamins C and E Carcinogenesis, March 1, 2005; 26(3): 605 - 612. [Abstract] [Full Text] [PDF]

				M. Chu, J. Guo, and C.-Y. Chen Long-term Exposure to Nicotine, via Ras Pathway, Induces Cyclin D1 to Stimulate G1 Cell Cycle Transition J. Biol. Chem., February 25, 2005; 280(8): 6369 - 6379. [Abstract] [Full Text] [PDF]

				J. G. Viniegra, N. Martinez, P. Modirassari, J. H. Losa, C. P. Cobo, V. J. S.-A. Lobo, C. I. A. Luquero, L. Alvarez-Vallina, S. Ramon y Cajal, J. M. Rojas, et al. Full Activation of PKB/Akt in Response to Insulin or Ionizing Radiation Is Mediated through ATM J. Biol. Chem., February 11, 2005; 280(6): 4029 - 4036. [Abstract] [Full Text] [PDF]

				G. V. Thomas, S. Horvath, B. L. Smith, K. Crosby, L. A. Lebel, M. Schrage, J. Said, J. De Kernion, R. E. Reiter, and C. L. Sawyers Antibody-Based Profiling of the Phosphoinositide 3-Kinase Pathway in Clinical Prostate Cancer Clin. Cancer Res., December 15, 2004; 10(24): 8351 - 8356. [Abstract] [Full Text] [PDF]

				J.-M. Peng, S.-M. Liang, and C.-M. Liang VP1 of Foot-and-Mouth Disease Virus Induces Apoptosis via the Akt Signaling Pathway J. Biol. Chem., December 10, 2004; 279(50): 52168 - 52174. [Abstract] [Full Text] [PDF]

				Y. L. Chen, P. Y. Law, and H. H. Loh Inhibition of Akt/Protein Kinase B Signaling by Naltrindole in Small Cell Lung Cancer Cells Cancer Res., December 1, 2004; 64(23): 8723 - 8730. [Abstract] [Full Text] [PDF]

				D. J. VanderWeele, R. Zhou, and C. M. Rudin Akt up-regulation increases resistance to microtubule-directed chemotherapeutic agents through mammalian target of rapamycin Mol. Cancer Ther., December 1, 2004; 3(12): 1605 - 1613. [Abstract] [Full Text] [PDF]

				H. W. Kim, I. K. Park, C. S. Cho, K. H. Lee, G. R. Beck Jr., N. H. Colburn, and M. H. Cho Aerosol Delivery of Glucosylated Polyethylenimine/Phosphatase and Tensin Homologue Deleted on Chromosome 10 Complex Suppresses Akt Downstream Pathways in the Lung of K-ras Null Mice Cancer Res., November 1, 2004; 64(21): 7971 - 7976. [Abstract] [Full Text] [PDF]

				B. R. Balsara, J. Pei, Y. Mitsuuchi, R. Page, A. Klein-Szanto, H. Wang, M. Unger, and J. R. Testa Frequent activation of AKT in non-small cell lung carcinomas and preneoplastic bronchial lesions Carcinogenesis, November 1, 2004; 25(11): 2053 - 2059. [Abstract] [Full Text] [PDF]

				H.-Y. Lee, H. Moon, K.-H. Chun, Y.-S. Chang, K. Hassan, L. Ji, R. Lotan, F. R. Khuri, and W. K. Hong Effects of Insulin-like Growth Factor Binding Protein-3 and Farnesyltransferase Inhibitor SCH66336 on Akt Expression and Apoptosis in Non-Small-Cell Lung Cancer Cells J Natl Cancer Inst, October 20, 2004; 96(20): 1536 - 1548. [Abstract] [Full Text] [PDF]

				S. Tracy, T. Mukohara, M. Hansen, M. Meyerson, B. E. Johnson, and P. A. Janne Gefitinib Induces Apoptosis in the EGFRL858R Non-Small-Cell Lung Cancer Cell Line H3255 Cancer Res., October 15, 2004; 64(20): 7241 - 7244. [Abstract] [Full Text] [PDF]

				O. David, J. Jett, H. LeBeau, G. Dy, J. Hughes, M. Friedman, and A. R. Brody Phospho-Akt Overexpression in Non-Small Cell Lung Cancer Confers Significant Stage-Independent Survival Disadvantage Clin. Cancer Res., October 15, 2004; 10(20): 6865 - 6871. [Abstract] [Full Text] [PDF]

				L. A. deGraffenried, L. Fulcher, W. E. Friedrichs, V. Grunwald, R. B. Ray, and M. Hidalgo Reduced PTEN expression in breast cancer cells confers susceptibility to inhibitors of the PI3 kinase/Akt pathway Ann. Onc., October 1, 2004; 15(10): 1510 - 1516. [Abstract] [Full Text] [PDF]

				G. Tell, A. Pines, F. Arturi, L. Cesaratto, E. Adamson, C. Puppin, I. Presta, D. Russo, S. Filetti, and G. Damante Control of Phosphatase and Tensin Homolog (PTEN) Gene Expression in Normal and Neoplastic Thyroid Cells Endocrinology, October 1, 2004; 145(10): 4660 - 4666. [Abstract] [Full Text] [PDF]

				M. Pold, K. Krysan, A. Pold, M. Dohadwala, N. Heuze-Vourc'h, J. T. Mao, K. L. Riedl, S. Sharma, and S. M. Dubinett Cyclooxygenase-2 Modulates the Insulin-Like Growth Factor Axis in Non-Small-Cell Lung Cancer Cancer Res., September 15, 2004; 64(18): 6549 - 6555. [Abstract] [Full Text] [PDF]

				F. Cappuzzo, E. Magrini, G. L. Ceresoli, S. Bartolini, E. Rossi, V. Ludovini, V. Gregorc, C. Ligorio, A. Cancellieri, S. Damiani, et al. Akt Phosphorylation and Gefitinib Efficacy in Patients With Advanced Non-Small-Cell Lung Cancer J Natl Cancer Inst, August 4, 2004; 96(15): 1133 - 1141. [Abstract] [Full Text] [PDF]

				B. Bartling, J.-Y. Yang, D. Michod, C. Widmann, R. Lewensohn, and B. Zhivotovsky RasGTPase-activating protein is a target of caspases in spontaneous apoptosis of lung carcinoma cells and in response to etoposide Carcinogenesis, June 1, 2004; 25(6): 909 - 921. [Abstract] [Full Text] [PDF]

				S. Tanno, N. Yanagawa, A. Habiro, K. Koizumi, Y. Nakano, M. Osanai, Y. Mizukami, T. Okumura, J. R. Testa, and Y. Kohgo Serine/Threonine Kinase AKT Is Frequently Activated in Human Bile Duct Cancer and Is Associated with Increased Radioresistance Cancer Res., May 15, 2004; 64(10): 3486 - 3490. [Abstract] [Full Text] [PDF]

				J. M. Kurie Role of Protein Kinase B-Dependent Signaling in Lung Tumorigenesis Chest, May 1, 2004; 125(5_suppl): 141S - 144S. [Abstract] [Full Text] [PDF]

				S. S. Castillo, J. Brognard, P. A. Petukhov, C. Zhang, J. Tsurutani, C. A. Granville, M. Li, M. Jung, K. A. West, J. G. Gills, et al. Preferential Inhibition of Akt and Killing of Akt-Dependent Cancer Cells by Rationally Designed Phosphatidylinositol Ether Lipid Analogues Cancer Res., April 15, 2004; 64(8): 2782 - 2792. [Abstract] [Full Text] [PDF]

				J. K. Park, Y. M. Chung, B.-G. Kim, Y.-A Yoo, B.-S. Yang, J. S. Kim, and Y. D. Yoo N'-(phenyl-pyridin-2-yl-methylene)-hydrazine carbodithioic acid methyl ester enhances radiation-induced cell death by targeting Bcl-2 against human lung carcinoma cells Mol. Cancer Ther., April 1, 2004; 3(4): 403 - 407. [Abstract] [Full Text] [PDF]

				A. Dowlati, D. Nethery, and J. A. Kern Combined inhibition of epidermal growth factor receptor and JAK/STAT pathways results in greater growth inhibition in vitro than single agent therapy Mol. Cancer Ther., April 1, 2004; 3(4): 459 - 463. [Abstract] [Full Text] [PDF]

				K. M. Vasudevan, S. Gurumurthy, and V. M. Rangnekar Suppression of PTEN Expression by NF-{kappa}B Prevents Apoptosis Mol. Cell. Biol., February 1, 2004; 24(3): 1007 - 1021. [Abstract] [Full Text] [PDF]

				D. M. Nguyen, G. A. Chen, R. Reddy, W. Tsai, W. D. Schrump, G. Cole Jr, and D. S. Schrump Potentiation of paclitaxel cytotoxicity in lung and esophageal cancer cells by pharmacologic inhibition of the phosphoinositide 3-kinase/protein kinase B (Akt)-mediated signaling pathway J. Thorac. Cardiovasc. Surg., February 1, 2004; 127(2): 365 - 375. [Abstract] [Full Text] [PDF]

				K. A. West, I. R. Linnoila, S. A. Belinsky, C. C. Harris, and P. A. Dennis Tobacco Carcinogen-Induced Cellular Transformation Increases Activation of the Phosphatidylinositol 3'-Kinase/Akt Pathway in Vitro and in Vivo Cancer Res., January 15, 2004; 64(2): 446 - 451. [Abstract] [Full Text] [PDF]

				M. Sumitomo, T. Asano, J. Asakuma, T. Asano, A. Horiguchi, and M. Hayakawa ZD1839 Modulates Paclitaxel Response in Renal Cancer by Blocking Paclitaxel-Induced Activation of the Epidermal Growth Factor Receptor-Extracellular Signal-Regulated Kinase Pathway Clin. Cancer Res., January 15, 2004; 10(2): 794 - 801. [Abstract] [Full Text] [PDF]

				K. Okudela, H. Hayashi, T. Ito, T. Yazawa, T. Suzuki, Y. Nakane, H. Sato, H. Ishi, X. KeQin, A. Masuda, et al. K-ras Gene Mutation Enhances Motility of Immortalized Airway Cells and Lung Adenocarcinoma Cells via Akt Activation: Possible Contribution to Non-Invasive Expansion of Lung Adenocarcinoma Am. J. Pathol., January 1, 2004; 164(1): 91 - 100. [Abstract] [Full Text] [PDF]

				A. Holleman, M. L. d. Boer, K. M. Kazemier, G. E. Janka-Schaub, and R. Pieters Resistance to different classes of drugs is associated with impaired apoptosis in childhood acute lymphoblastic leukemia Blood, December 15, 2003; 102(13): 4541 - 4546. [Abstract] [Full Text] [PDF]

				A. Jetzt, J. A. Howe, M. T. Horn, E. Maxwell, Z. Yin, D. Johnson, and C. C. Kumar Adenoviral-Mediated Expression of a Kinase-Dead Mutant of Akt Induces Apoptosis Selectively in Tumor Cells and Suppresses Tumor Growth in Mice Cancer Res., October 15, 2003; 63(20): 6697 - 6706. [Abstract] [Full Text] [PDF]

				G. Sithanandam, G. T. Smith, A. Masuda, T. Takahashi, L. M. Anderson, and L. W. Fornwald Cell cycle activation in lung adenocarcinoma cells by the ErbB3/phosphatidylinositol 3-kinase/Akt pathway Carcinogenesis, October 1, 2003; 24(10): 1581 - 1592. [Abstract] [Full Text] [PDF]

				B. B.Y. Ma, R. G. Bristow, J. Kim, and L. L. Siu Combined-Modality Treatment of Solid Tumors Using Radiotherapy and Molecular Targeted Agents J. Clin. Oncol., July 15, 2003; 21(14): 2760 - 2776. [Abstract] [Full Text] [PDF]