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.
Highlights
Soft tissue sarcomas are a heterogeneous group of solid malignant tumors having various histologies and commonly characterized by aggressive characteristics locally and in distant metastases [1,2]
Mounting evidence indicates that signal transducers and activators of transcription-3 (STAT-3) activation contributes to proliferation and oncogenesis by modulating the expression of a variety of genes required for tumor cell survival, proliferation and angiogenesis, as well as invasion and metastasis [43] but STAT-3 inhibition leads to suppression of the growth of numerous cancers in vitro and in vivo [29,44,45]
It is suggested that targeted disruption of STAT-3 could be one potential to proliferation and oncogenesis by modulating the expression of a variety of genes required for tumor cell survival, proliferation and angiogenesis, as well as invasion and metastasis [43] but STAT-3 inhibition leads to suppression of the growth of numerous cancers in vitro and in vivo [29,44,45]
Summary
Soft tissue sarcomas are a heterogeneous group of solid malignant tumors having various histologies and commonly characterized by aggressive characteristics locally and in distant metastases [1,2]. The provirus integration site for moloney murine leukemia virus (Pim) kinases, composing of Pim-1, Pim-2 and Pim-3, are active serine (S)/threonine (T) kinases which are highly homologous with overlapping functions and substrate specificities [8] They modulate the activity of a variety of downstream effector proteins, such as, eukaryotic translation initiation factor 4E binding protein-1 (4EBP-1), mammalian target of rapamycin (mTOR), the 40S ribosomal subunit S6 protein, p70 S6 kinase (p70S6K), signal transducers and activators of transcription-3 (STAT-3), AMP-actuated protein kinase (AMPK), involved in the control of cell cycle, survival, transcription, translation, drug resistance and signaling within the microenvironment [8,9,10,11]. Pim kinases contain a unique ATP-binding pocket, which has resulted in the development of highly selective pan-Pim inhibitors such as AZD1208 [18,19]
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