Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation
- PMID: 11358816
Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation
Abstract
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.
Similar articles
-
Role of the phosphatidylinositol 3'-kinase/PTEN/Akt kinase pathway in tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in non-small cell lung cancer cells.Cancer Res. 2002 Sep 1;62(17):4929-37. Cancer Res. 2002. PMID: 12208743
-
Serine/threonine kinase AKT is frequently activated in human bile duct cancer and is associated with increased radioresistance.Cancer Res. 2004 May 15;64(10):3486-90. doi: 10.1158/0008-5472.CAN-03-1788. Cancer Res. 2004. PMID: 15150102
-
Pro-survival function of Akt/protein kinase B in prostate cancer cells. Relationship with TRAIL resistance.J Biol Chem. 2001 Oct 19;276(42):38361-9. doi: 10.1074/jbc.M103321200. Epub 2001 Jul 18. J Biol Chem. 2001. Retraction in: J Biol Chem. 2002 Aug 16;277(33):30408. PMID: 11461904 Retracted.
-
Mechanism of protein kinase B activation by insulin/insulin-like growth factor-1 revealed by specific inhibitors of phosphoinositide 3-kinase--significance for diabetes and cancer.Pharmacol Ther. 1999 May-Jun;82(2-3):409-25. doi: 10.1016/s0163-7258(98)00071-0. Pharmacol Ther. 1999. PMID: 10454216 Review.
-
The activation of Akt/PKB signaling pathway and cell survival.J Cell Mol Med. 2005 Jan-Mar;9(1):59-71. doi: 10.1111/j.1582-4934.2005.tb00337.x. J Cell Mol Med. 2005. PMID: 15784165 Free PMC article. Review.
Cited by
-
Synergistic inhibition of colon cancer cell growth with nanoemulsion-loaded paclitaxel and PI3K/mTOR dual inhibitor BEZ235 through apoptosis.Int J Nanomedicine. 2016 May 5;11:1947-58. doi: 10.2147/IJN.S100744. eCollection 2016. Int J Nanomedicine. 2016. PMID: 27226714 Free PMC article.
-
m6A Reader YTHDC2 Promotes Radiotherapy Resistance of Nasopharyngeal Carcinoma via Activating IGF1R/AKT/S6 Signaling Axis.Front Oncol. 2020 Jul 31;10:1166. doi: 10.3389/fonc.2020.01166. eCollection 2020. Front Oncol. 2020. PMID: 32850334 Free PMC article.
-
PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes.Acta Pharmacol Sin. 2012 Dec;33(12):1441-58. doi: 10.1038/aps.2012.72. Epub 2012 Sep 17. Acta Pharmacol Sin. 2012. PMID: 22983389 Free PMC article. Review.
-
Cbl-b-regulated extracellular signal-regulated kinase signaling is involved in the shikonin-induced apoptosis of lung cancer cells in vitro.Exp Ther Med. 2015 Apr;9(4):1265-1270. doi: 10.3892/etm.2015.2283. Epub 2015 Feb 10. Exp Ther Med. 2015. PMID: 25780420 Free PMC article.
-
New molecularly targeted therapies for lung cancer.J Clin Invest. 2007 Oct;117(10):2740-50. doi: 10.1172/JCI31809. J Clin Invest. 2007. PMID: 17909619 Free PMC article. Review.
MeSH terms
Substances
LinkOut - more resources
Other Literature Sources
Medical
Molecular Biology Databases
Research Materials
Miscellaneous