Inhibiting PLK1 induces autophagy of acute myeloid leukemia cells via mammalian target of rapamycin pathway dephosphorylation.

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.
Authors	Yan-Fang Tao, Zhi-Heng Li, Wei-Wei Du, Li-Xiao Xu, Jun-Li Ren, Xiao-Lu Li, Fang Fang, Yi Xie, Mei Li, Guang-Hui Qian, Yan-Hong Li, Yi-Ping Li, Gang Li, Yi Wu, Xing Feng, Jian Wang, Wei-Qi He, Shao-Yan Hu, Jun Lu, Jian Pan
Journal	Oncology reports (Oncol Rep) Vol. 37 Issue 3 Pg. 1419-1429 (Mar 2017) ISSN: 1791-2431 [Electronic] Greece
PMID	28184925 (Publication Type: Journal Article)
Chemical References	Biomarkers, Tumor Cell Cycle Proteins Proto-Oncogene Proteins RNA, Messenger RNA, Small Interfering MTOR protein, human Protein Serine-Threonine Kinases TOR Serine-Threonine Kinases polo-like kinase 1
Topics	Animals Autophagy Biomarkers, Tumor (genetics, metabolism) Blotting, Western Cell Cycle Proteins (antagonists & inhibitors, genetics, metabolism) Cell Proliferation Child Female Humans Leukemia, Myeloid, Acute (genetics, metabolism, pathology) Male Mice Neoplasm Staging Phosphorylation Prognosis Protein Serine-Threonine Kinases (antagonists & inhibitors, genetics, metabolism) Proto-Oncogene Proteins (antagonists & inhibitors, genetics, metabolism) RNA, Messenger (genetics) RNA, Small Interfering (genetics) Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Survival Rate TOR Serine-Threonine Kinases (genetics, metabolism) Tumor Cells, Cultured Xenograft Model Antitumor Assays

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