Pan-Pim Kinase Inhibitor AZD1208 Suppresses Tumor Growth and Synergistically Interacts with Akt Inhibition in Gastric Cancer Cells
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Purpose Pim kinases are highly conserved serine/threonine kinases, and different expression patterns of each isoform (Pim-1, Pim-2, and Pim-3) have been observed in various types of human cancers, including gastric cancer. AZD1208 is a potent and selective inhibitor that affects all three isoforms of Pim. We investigated the effects of AZD1208 as a single agent and in combination with an Akt inhibitor in gastric cancer cells. Materials and Methods The antitumor activity of AZD1208 with/without an Akt inhibitor was evaluated in a large panel of gastric cancer cell lines through growth inhibition assays. The underlying mechanism was also examined by western blotting, immunofluorescence assay, and cell cycle analysis. Results AZD1208 treatment decreased gastric cancer cell proliferation rates and induced autophagy only in long-term culture systems. Light chain 3B (LC3B), a marker of autophagy, was increased in sensitive cells in a dose-dependent manner with AZD1208 treatment, which suggested that the growth inhibition effect of AZD1208 was achieved through autophagy, not apoptosis. Moreover, we found that cells damaged by Pim inhibition were repaired by activation of the DNA damage repair pathway, which promoted cell survival and led the cells to become resistant to AZD1208. We also confirmed that the combination of an Akt inhibitor with AZD1208 produced a highly synergistic effect in gastric cancer cell lines. Conclusion Treatment with AZD1208 alone induced considerable cell death through autophagy in gastric cancer cells. Moreover, the combination of AZD1208 with an Akt inhibitor showed synergistic antitumor effects through regulation of the DNA damage repair pathway.
Abstract
Purpose Pim kinases are highly conserved serine/threonine kinases, and different expression patterns of each isoform (Pim-1, Pim-2, and Pim-3) have been observed in various types of human cancers, including gastric cancer. AZD1208 is a potent and selective inhibitor that affects all three isoforms of Pim. We investigated the effects of AZD1208 as a single agent and in combination with an Akt inhibitor in gastric cancer cells. Materials and Methods The antitumor activity of AZD1208 with/without an Akt inhibitor was evaluated in a large panel of gastric cancer cell lines through growth inhibition assays. The underlying mechanism was also examined by western blotting, immunofluorescence assay, and cell cycle analysis. Results AZD1208 treatment decreased gastric cancer cell proliferation rates and induced autophagy only in long-term culture systems. Light chain 3B (LC3B), a marker of autophagy, was increased in sensitive cells in a dose-dependent manner with AZD1208 treatment, which suggested that the growth inhibition effect of AZD1208 was achieved through autophagy, not apoptosis. Moreover, we found that cells damaged by Pim inhibition were repaired by activation of the DNA damage repair pathway, which promoted cell survival and led the cells to become resistant to AZD1208. We also confirmed that the combination of an Akt inhibitor with AZD1208 produced a highly synergistic effect in gastric cancer cell lines. Conclusion Treatment with AZD1208 alone induced considerable cell death through autophagy in gastric cancer cells. Moreover, the combination of AZD1208 with an Akt inhibitor showed synergistic antitumor effects through regulation of the DNA damage repair pathway.
참고문헌 (30)
- Narlik-Grassow M, "The PIM family of serine", threonine kinases in cancer, 2014, pp.34, 136~159
- Brault L, "PIM serine", threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers, 2010, pp.95, 1004~1015
- Nawijn MC, "For better or for worse : the role of Pim oncogenes in tumorigenesis", Nat Rev Cancer, 11, pp.23~34 (2011)
- Warnecke-Eberz U, "Prognostic impact of protein overexpression of the proto-oncogene PIM-1 in gastric cancer", Anticancer Res, 29, pp.4451~4455 (2009)
- Zheng HC, "Aberrant Pim-3 expression is involved in gastric adenoma-adenocarcinoma sequence and cancer progression", J Cancer Res Clin Oncol, 134, pp.481~488 (2008)
- Khanna P, "The JAK", STAT signaling cascade in gastric carcinoma(Review), 2015, pp.47, 1617~1626
- Vivanco I, "The phosphatidylinositol 3-Kinase AKT pathway in human cancer", Nat Rev Cancer, 2, pp.489~501 (2002)
- LoPiccolo J, "Targeting the PI3K", Akt, Drug Resist Updat, pp.2008, 11[DOI]
- Chandarlapaty S, "AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity", Cancer Cell, 19, pp.58~71 (2011)
- Muranen T, "Inhibition of PI3K", mTOR leads to adaptive resistance in matrix-attached cancer cells, 2012, pp.21, 227~239
- Altomare DA, "Homeostasis and the importance for a balance between AKT", mTOR activity and intracellular signaling, 2012, pp.19, 3748~3762
- Amaravadi R, "The survival kinases Akt and Pim as potential pharmacological targets", J Clin Invest, 115, pp.2618~2624 (2005)
- Hammerman PS, "Pim and Akt oncogenes are independent regulators of hematopoietic cell growth and survival", Blood, 105, pp.4477~4483 (2005)
- Cen B, "Elevation of receptor tyrosine kinases by small molecule AKT inhibitors in prostate cancer is mediated by Pim-1", Cancer Res, 73, pp.3402~3411 (2013)
- Meja K, "PIM and AKT kinase inhibitors show synergistic cytotoxicity in acute myeloid leukaemia that is associated with convergence on mTOR and MCL1 pathways", Br J Haematol, 167, pp.69~79 (2014)
- Keeton EK, "AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia", Blood, 123, pp.905~913 (2014)
- Dakin LA, "Discovery of novel benzylidene-1, 3-thiazolidine-2, 4-diones as potent and selective inhibitors of the PIM-1, PIM-2, and PIM-3 protein kinases", Bioorg Med Chem Lett, 22, pp.4599~4604 (2012)
- Davies BR, "Preclinical pharmacology of AZD5363, an inhibitor of AKT : pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background", Mol Cancer Ther, 11, pp.873~887 (2012)
- Ja Lok Ku, "Biology of SNU Cell Lines", Cancer Research and Treatment, 37(1), pp.1~19 (2005), 대한암학회
- 강소영, "TGF-β Suppresses COX-2 Expression by Tristetraprolin-Mediated RNA Destabilization in A549 Human Lung Cancer Cells", Cancer Research and Treatment, 47(1), pp.101~109 (2015), 대한암학회[DOI]
- Wang Z, "Pim-2 phosphorylation of p21(Cip1", WAF1)enhances its stability and inhibits cell proliferation in HCT116 cells, 2010, pp.42, 1030~1038
- Bartek J, "DNA damage checkpoints : from initiation to recovery or adaptation", Curr Opin Cell Biol, 19, pp.238~245 (2007)
- Zirkin S, "The PIM-2 kinase is an essential component of the ultraviolet damage response that acts upstream to E2F-1 and ATM", J Biol Chem, 288, pp.21770~21783 (2013)
- Helleday T, "DNA repair pathways as targets for cancer therapy", Nat Rev Cancer, 8, pp.193~204 (2008)
- Ang KL, "Upregulated Akt signaling adjacent to gastric cancers : implications for screening and chemoprevention", Cancer Lett, 225, pp.53~59 (2005)
- Xu N, "Akt : a double-edged sword in cell proliferation and genome stability", J Oncol, 2012, pp.951724~ (2012)
- Blanco-Aparicio C, "Pim 1 kinase inhibitor ETP-45299 suppresses cellular proliferation and synergizes with PI3K inhibition", Cancer Lett, 300, pp.145~153 (2011)
- Cervantes-Gomez F, "Biological effects of the Pim kinase inhibitor, SGI-1776, in multiple myeloma", Clin Lymphoma Myeloma Leuk, 13(Suppl 2), pp.S317~S329 (2013)
- Crighton D, "DRAM, a p53-induced modulator of autophagy, is critical for apoptosis", Cell, 126, pp.121~134 (2006)
- Fruman DA, "PI3K and cancer : lessons, challenges and opportunities", Nat Rev Drug Discov, 13, pp.140~156 (2014)