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Inhibiting PLK1 induces autophagy of acute myeloid leukemia cells via mammalian target of rapamycin pathway dephosphorylation
- Source :
- Oncology Reports
- Publication Year :
- 2017
- Publisher :
- Spandidos Publications, 2017.
-
Abstract
- Decreased autophagy is accompanied by the development of a myeloproliferative state or acute myeloid leukemia (AML). AML cells are often sensitive to autophagy‑inducing stimuli, prompting the idea that targeting autophagy can be useful in AML cytotoxic therapy. AML NB4 cells overexpressing microtubule-associated protein 1 light chain 3-green fluorescent protein were screened with 69 inhibitors to analyze autophagy activity. AML cells were treated with the polo-like kinase 1 (PLK1) inhibitors RO3280 and BI2536 before autophagy analysis. Cleaved LC3 (LC3-II) and the phosphorylation of mammalian target of rapamycin (mTOR), adenosine monophosphate-activated protein kinase, and Unc-51-like kinase 1 during autophagy was detected with western blotting. Autophagosomes were detected using transmission electron microscopy. Several inhibitors had promising autophagy inducer effects: BI2536, MLN0905, SK1-I, SBE13 HCL and RO3280. Moreover, these inhibitors all targeted PLK1. Autophagy activity was increased in the NB4 cells treated with RO3280 and BI2536. Inhibition of PLK1 expression in NB4, K562 and HL-60 leukemia cells with RNA interference increased LC3-II and autophagy activity. The phosphorylation of mTOR was reduced significantly in NB4 cells treated with RO3280 and BI2536, and was also reduced significantly when PLK1 expression was downregulated in the NB4, K562 and HL-60 cells. We demonstrate that PLK1 inhibition induces AML cell autophagy and that it results in mTOR dephosphorylation. These results may provide new insights into the molecular mechanism of PLK1 in regulating autophagy.
- Subjects :
- Male
0301 basic medicine
Cancer Research
Cell Cycle Proteins
Mice
0302 clinical medicine
hemic and lymphatic diseases
Tumor Cells, Cultured
Phosphorylation
RNA, Small Interfering
Child
Reverse Transcriptase Polymerase Chain Reaction
TOR Serine-Threonine Kinases
RO3280
Myeloid leukemia
Articles
General Medicine
Cell cycle
Prognosis
Cell biology
Survival Rate
Leukemia, Myeloid, Acute
mTOR phosphorylation
Oncology
030220 oncology & carcinogenesis
polo-like kinase 1
Female
Signal Transduction
autophagy
Programmed cell death
Blotting, Western
Protein Serine-Threonine Kinases
Biology
Real-Time Polymerase Chain Reaction
03 medical and health sciences
Proto-Oncogene Proteins
Biomarkers, Tumor
Animals
Humans
RNA, Messenger
Protein kinase A
PI3K/AKT/mTOR pathway
Cell Proliferation
Neoplasm Staging
BI2536
Autophagy
pediatric acute myeloid leukemia
Xenograft Model Antitumor Assays
030104 developmental biology
Cancer research
K562 cells
Subjects
Details
- ISSN :
- 17912431 and 1021335X
- Volume :
- 37
- Database :
- OpenAIRE
- Journal :
- Oncology Reports
- Accession number :
- edsair.doi.dedup.....7269432df7b64ff494d777d80d680ee1