Oncotarget, 2015-11, Vol.6 (35), p.37930-37947
2015
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- Autor(en) / Beteiligte
- Titel
- The novel combination of dual mTOR inhibitor AZD2014 and pan-PIM inhibitor AZD1208 inhibits growth in acute myeloid leukemia via HSF pathway suppression
- Ist Teil von
- Oncotarget, 2015-11, Vol.6 (35), p.37930-37947
- Ort / Verlag
- United States: Impact Journals LLC
- Erscheinungsjahr
- 2015
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Mammalian target of rapamycin (mTOR) signaling is a critical pathway in the biology of acute myeloid leukemia (AML). Proviral integration site for moloney murine leukemia virus (PIM) serine/threonine kinase signaling takes part in various pathways exerting tumorigenic properties. We hypothesized that the combination of a PIM kinase inhibitor with an mTOR inhibitor might have complementary growth-inhibitory effects against AML. The simultaneous inhibition of the PIM kinase by pan-PIM inhibitor AZD1208 and of mTOR by selective mTORC1/2 dual inhibitor AZD2014 exerted anticancer properties in AML cell lines and in cells derived from primary AML samples with or without supportive stromal cell co-culture, leading to suppressed proliferation and increased apoptosis. The combination of AZD1208 and AZD2014 rapidly activated AMPKα, a negative regulator of translation machinery through mTORC1/2 signaling in AML cells; profoundly inhibited AKT and 4EBP1 activation; and suppressed polysome formation. Inhibition of both mTOR and PIM counteracted induction of heat-shock family proteins, uncovering the master negative regulation of heat shock factor 1 (HSF1), the dominant transcription factor controlling cellular stress responses. The novel combination of the dual mTOR inhibitor and pan-PIM inhibitor synergistically inhibited AML growth by effectively reducing protein synthesis through heat shock factor pathway suppression.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1949-2553eISSN: 1949-2553DOI: 10.18632/oncotarget.6122Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4741975
- Format
- –
- Schlagworte
- Apoptosis - drug effects, Biphenyl Compounds - pharmacology, Blotting, Western, Cell Proliferation - drug effects, DNA-Binding Proteins - genetics, DNA-Binding Proteins - metabolism, Drug Therapy, Combination, Flow Cytometry, Heat Shock Transcription Factors, Humans, Leukemia, Myeloid, Acute - drug therapy, Leukemia, Myeloid, Acute - genetics, Leukemia, Myeloid, Acute - pathology, Morpholines - pharmacology, Phosphoproteins, Phosphorylation - drug effects, Protein Kinase Inhibitors - pharmacology, Proto-Oncogene Proteins c-pim-1 - antagonists & inhibitors, Real-Time Polymerase Chain Reaction, Research Paper, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger - genetics, Signal Transduction - drug effects, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Thiazolidines - pharmacology, TOR Serine-Threonine Kinases - antagonists & inhibitors, Transcription Factors - genetics, Transcription Factors - metabolism, Tumor Cells, Cultured