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AZD1208, a Pan-Pim Kinase Inhibitor, Has Anti-Growth Effect on 93T449 Human Liposarcoma Cells via Control of the Expression and Phosphorylation of Pim-3, mTOR, 4EBP-1, S6, STAT-3 and AMPK.
Int J Mol Sci 2019; 20(2)IJ

Abstract

Overexpression of Pim kinases has an oncogenic/pro-survival role in many hematological and solid cancers. AZD1208 is a pan-Pim kinase inhibitor that has anti-cancer and anti-adipogenic actions. Here, we investigated the effects of AZD1208 on the growth of 93T449 cells, a differentiated human liposarcoma cell line. At 20 µM, AZD1208 was cytotoxic (cytostatic) but not apoptotic, reducing cell survival without DNA fragmentation, caspase activation or increasing cells in the sub G1 phase; known apoptotic parameters. Notably, AZD1208 reduced phosphorylation of signal transducer and activator of transcription-3 (STAT-3) in 93T449 cells. STAT-3 inhibition by AG490, a JAK2/STAT-3 inhibitor similarly reduced cell survival. AZD1208 down-regulated phosphorylation of mammalian target of rapamycin (mTOR) and ribosomal S6 while up-regulated eukaryotic initiation factor-2α (eIF-2α). In addition, AZD1208 induced a LKB-1-independent AMPK activation, which was crucial for its cytostatic effect, as knock-down of AMPK greatly blocked AZD1208s ability to reduce cell survival. AZD1208 had no effect on expression of two members of Pim kinase family (Pim-1 and Pim-3) but inhibited phosphorylation of 4EBP-1, a downstream effector of Pim kinases. Importantly, a central role for Pim-3 in the actions of AZD1208 was confirmed by knock-down, which not only reduced 93T449 cell survival but also led to the inhibition of 4EBP-1, mTOR, eIF-2α and STAT-3, along with the activation of AMPK. In summary, this is the first report demonstrating that AZD1208 inhibits growth of liposarcoma cells and that this activity is mediated through Pim-3 kinase, STAT-3, mTOR, S6 and AMPK expression and phosphorylation pathways.

Authors+Show Affiliations

Department of Molecular Medicine, College of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-gu, Daegu 42601, Korea. aydaegu@gmail.com.Department of Molecular Medicine, College of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-gu, Daegu 42601, Korea. vinbavin@gmail.com.Comparative Biomedical Sciences, Royal Veterinary College, London NW1 0TU, UK. dbishopbailey@rvc.ac.uk.Department of Molecular Medicine, College of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-gu, Daegu 42601, Korea. jangbc123@gw.kmu.ac.kr.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30654529

Citation

Yadav, Anil Kumar, et al. "AZD1208, a Pan-Pim Kinase Inhibitor, Has Anti-Growth Effect On 93T449 Human Liposarcoma Cells Via Control of the Expression and Phosphorylation of Pim-3, mTOR, 4EBP-1, S6, STAT-3 and AMPK." International Journal of Molecular Sciences, vol. 20, no. 2, 2019.
Yadav AK, Kumar V, Bailey DB, et al. AZD1208, a Pan-Pim Kinase Inhibitor, Has Anti-Growth Effect on 93T449 Human Liposarcoma Cells via Control of the Expression and Phosphorylation of Pim-3, mTOR, 4EBP-1, S6, STAT-3 and AMPK. Int J Mol Sci. 2019;20(2).
Yadav, A. K., Kumar, V., Bailey, D. B., & Jang, B. C. (2019). AZD1208, a Pan-Pim Kinase Inhibitor, Has Anti-Growth Effect on 93T449 Human Liposarcoma Cells via Control of the Expression and Phosphorylation of Pim-3, mTOR, 4EBP-1, S6, STAT-3 and AMPK. International Journal of Molecular Sciences, 20(2), doi:10.3390/ijms20020363.
Yadav AK, et al. AZD1208, a Pan-Pim Kinase Inhibitor, Has Anti-Growth Effect On 93T449 Human Liposarcoma Cells Via Control of the Expression and Phosphorylation of Pim-3, mTOR, 4EBP-1, S6, STAT-3 and AMPK. Int J Mol Sci. 2019 Jan 16;20(2) PubMed PMID: 30654529.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - AZD1208, a Pan-Pim Kinase Inhibitor, Has Anti-Growth Effect on 93T449 Human Liposarcoma Cells via Control of the Expression and Phosphorylation of Pim-3, mTOR, 4EBP-1, S6, STAT-3 and AMPK. AU - Yadav,Anil Kumar, AU - Kumar,Vinoth, AU - Bailey,David Bishop, AU - Jang,Byeong-Churl, Y1 - 2019/01/16/ PY - 2018/12/21/received PY - 2019/01/09/accepted PY - 2019/1/19/entrez PY - 2019/1/19/pubmed PY - 2019/4/30/medline KW - 93T449 KW - AMPK KW - AZD1208 KW - Pim-3 KW - STAT-3 JF - International journal of molecular sciences JO - Int J Mol Sci VL - 20 IS - 2 N2 - Overexpression of Pim kinases has an oncogenic/pro-survival role in many hematological and solid cancers. AZD1208 is a pan-Pim kinase inhibitor that has anti-cancer and anti-adipogenic actions. Here, we investigated the effects of AZD1208 on the growth of 93T449 cells, a differentiated human liposarcoma cell line. At 20 µM, AZD1208 was cytotoxic (cytostatic) but not apoptotic, reducing cell survival without DNA fragmentation, caspase activation or increasing cells in the sub G1 phase; known apoptotic parameters. Notably, AZD1208 reduced phosphorylation of signal transducer and activator of transcription-3 (STAT-3) in 93T449 cells. STAT-3 inhibition by AG490, a JAK2/STAT-3 inhibitor similarly reduced cell survival. AZD1208 down-regulated phosphorylation of mammalian target of rapamycin (mTOR) and ribosomal S6 while up-regulated eukaryotic initiation factor-2α (eIF-2α). In addition, AZD1208 induced a LKB-1-independent AMPK activation, which was crucial for its cytostatic effect, as knock-down of AMPK greatly blocked AZD1208s ability to reduce cell survival. AZD1208 had no effect on expression of two members of Pim kinase family (Pim-1 and Pim-3) but inhibited phosphorylation of 4EBP-1, a downstream effector of Pim kinases. Importantly, a central role for Pim-3 in the actions of AZD1208 was confirmed by knock-down, which not only reduced 93T449 cell survival but also led to the inhibition of 4EBP-1, mTOR, eIF-2α and STAT-3, along with the activation of AMPK. In summary, this is the first report demonstrating that AZD1208 inhibits growth of liposarcoma cells and that this activity is mediated through Pim-3 kinase, STAT-3, mTOR, S6 and AMPK expression and phosphorylation pathways. SN - 1422-0067 UR - https://www.unboundmedicine.com/medline/citation/30654529/AZD1208_a_Pan_Pim_Kinase_Inhibitor_Has_Anti_Growth_Effect_on_93T449_Human_Liposarcoma_Cells_via_Control_of_the_Expression_and_Phosphorylation_of_Pim_3_mTOR_4EBP_1_S6_STAT_3_and_AMPK_ L2 - http://www.mdpi.com/resolver?pii=ijms20020363 DB - PRIME DP - Unbound Medicine ER -