PIP4K2A and PIP4K2C transcript levels are associated with cytogenetic risk and survival outcomes in acute myeloid leukemia

Lima, Keli; Coelho-Silva, Juan Luiz; Kinker, Gabriela Sarti; Pereira-Martins, Diego A; Traina, Fabı́ola; Fernandes, Pedro Augusto Carlos Magno; Markus, Regina Pekelmann; Lucena-Araújo, Antonio R.; Machado-Neto, João Agostinho

doi:10.1016/j.cancergen.2019.04.002

Cited by 25 publications

(33 citation statements)

References 43 publications

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“…It is a PIK from a family that contains three members: It phosphorylates the phosphatidyl-inositol (PtdIns)5P, producing PtdIns4,5P 2 (or PIP2), which is important for PIK signal transduction pathways ( McCrea and De Camilli, 2009 ; Fiume et al, 2015 ). The functions of PIP4K2C are poorly known, although mutations suggest that this kinase could be involved in cell proliferation and acute myeloblastic leukaemia ( Lima et al, 2019 ). However, it has been linked to the autophagic response (Vicinanza, 2015 #64).…”

Section: Discussionmentioning

confidence: 99%

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Novel Mechanism for an Old Drug: Phenazopyridine is a Kinase Inhibitor Affecting Autophagy and Cellular Differentiation

et al. 2021

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Phenazopyridine is a widely used drug against urinary tract pain. The compound has also been shown to enhance neural differentiation of pluripotent stem cells. However, its mechanism of action is not understood. Based on its chemical structure, we hypothesized that phenazopyridine could be a kinase inhibitor. Phenazopyridine was investigated in the following experimental systems: 1) activity of kinases in pluripotent stem cells; 2) binding to recombinant kinases, and 3) functional impact on pluripotent stem cells. Upon addition to pluripotent stem cells, phenazopyridine induced changes in kinase activities, particularly involving Mitogen-Activated Protein Kinases, Cyclin-Dependent Kinases, and AKT pathway kinases. To identify the primary targets of phenazopyridine, we screened its interactions with 401 human kinases. Dose-inhibition curves showed that three of these kinases interacted with phenazopyridine with sub-micromolar binding affinities: cyclin-G-associated kinase, and the two phosphatidylinositol kinases PI4KB and PIP4K2C, the latter being known for participating in pain induction. Docking revealed that phenazopyridine forms strong H-bonds with the hinge region of the ATP-binding pocket of these kinases. As previous studies suggested increased autophagy upon inhibition of the phosphatidyl-inositol/AKT pathway, we also investigated the impact of phenazopyridine on this pathway and found an upregulation. In conclusion, our study demonstrates for the first time that phenazopyridine is a kinase inhibitor, impacting notably phosphatidylinositol kinases involved in nociception.

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Section: Discussionmentioning

confidence: 99%

“…). The functions of PIP4K2C are poorly known, although mutations suggest that this kinase could be involved in cell proliferation and acute myeloblastic leukaemia (Lima et al, 2019). However, it has been linked to the autophagic response (Vicinanza, 2015 #64).…”

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confidence: 99%

Novel Mechanism for an Old Drug: Phenazopyridine is a Kinase Inhibitor Affecting Autophagy and Cellular Differentiation

et al. 2021

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“…PIP4K2A has a higher expression in healthy peripheral mononuclear cells derived from blood compared to cells from established leukemic cell lines 40 . Initial studies of different subtypes of PIP4Ks indicated a potential role of PIP4K2A as an anticancer target in leukemia 41 as it was shown that PIP4K2A knockdown in p53‐mutated tumors reduced the tumor size and increased the tumor‐free survival 42,43 . However, recent studies indicate a potential tumor‐suppressive role of PIP4K2A due to its silencing in leukemia and glioblastoma cells 40,44,45 .…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, it was concluded that PIP4K2C regulated the immune response in mammals. In humans, PIP4K2C gene transcripts were shown to correlate with the survival rate of adult patients with AML 43 . PIP4K2C has previously been identified as an off‐target to BI2536, a precursor of volasertib 50,51 .…”

Section: Discussionmentioning

confidence: 99%

Thermal proteome profiling identifies PIP4K2A and ZADH2 as off‐targets of Polo‐like kinase 1 inhibitor volasertib

et al. 2021

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Polo‐like kinase 1 (PLK1) is an important cell cycle kinase and an attractive target for anticancer treatments. An ATP‐competitive small molecular PLK1 inhibitor, volasertib, has reached phase III in clinical trials in patients with refractory acute myeloid leukemia as a combination treatment with cytarabine. However, severe side effects limited its use. The origin of the side effects is unclear and might be due to insufficient specificity of the drug. Thus, identifying potential off‐targets to volasertib is important for future clinical trials and for the development of more specific drugs. In this study, we used thermal proteome profiling (TPP) to identify proteome‐wide targets of volasertib. Apart from PLK1 and proteins regulated by PLK1, we identified about 200 potential volasertib off‐targets. Comparison of this result with the mass‐spectrometry analysis of volasertib‐treated cells showed that phosphatidylinositol phosphate and prostaglandin metabolism pathways are affected by volasertib. We confirmed that PIP4K2A and ZADH2—marker proteins for these pathways—are, indeed, stabilized by volasertib. PIP4K2A, however, was not affected by another PLK1 inhibitor onvansertib, suggesting that PIP4K2A is a true off‐target of volasertib. Inhibition of these proteins is known to impact both the immune response and fatty acid metabolism and could explain some of the side effects seen in volasertib‐treated patients.

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“…Different isoforms of mammalian PIP4K have been shown to be localized to different intracellular regions and regulate distinct cellular processes. PIP4K2A has been shown to be predominantly cytosolic and regulate cell proliferation and tumor progression (Ciruela et al, 2000;Jude et al, 2015;Lima et al, 2015Lima et al, , 2019Liao et al, 2016;Shin et al, 2019;Zhang et al, 2019). PIP4K2B is mainly nuclear and is also involved in regulating cell proliferation and tumor progression (Wang et al, 2010;Kouchi et al, 2011;Keune et al, 2013;Xu et al, 2016;Chauvin et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Conserved RNA Binding Activity of Phosphatidyl Inositol 5-Phosphate 4-Kinase (PIP4K2A)

Behari

Borkar

Vindu

et al. 2021

Front. Mol. Biosci.

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Plasmodium falciparum is a causative agent for malaria and has a complex life cycle in human and mosquito hosts. During its life cycle, the malarial parasite Plasmodium goes through different asexual and sexual stages, in humans and mosquitoes. Expression of stage-specific proteins is important for successful completion of its life cycle and requires tight gene regulation. In the case of Plasmodium, due to relative paucity of the transcription factors, it is postulated that posttranscriptional regulation plays an important role in stage-specific gene expression. Translation repression of specific set of mRNA has been reported in gametocyte stages of the parasite. A conserved element present in the 3′UTR of some of these transcripts was identified. Phosphatidylinositol 5-phosphate 4-kinase (PIP4K2A) was identified as the protein that associates with these RNA. We now show that the RNA binding activity of PIP4K2A is independent of its kinase activity. We also observe that PIP4K2A is imported into the parasite from the host on Plasmodium berghei and Toxoplasma gondii. The RNA binding activity of PIP4K2A seems to be conserved across species from Drosophila and C. elegans to humans, suggesting that the RNA binding activity of PIP4K may be important, and there may be host transcripts that may be regulated by PIP4K2A. These results identify a novel RNA binding role for PIP4K2A that may not only play a role in Plasmodium propagation but may also function in regulating gene expression in multicellular organisms.

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PIP4K2A and PIP4K2C transcript levels are associated with cytogenetic risk and survival outcomes in acute myeloid leukemia

Cited by 25 publications

References 43 publications

Novel Mechanism for an Old Drug: Phenazopyridine is a Kinase Inhibitor Affecting Autophagy and Cellular Differentiation

Novel Mechanism for an Old Drug: Phenazopyridine is a Kinase Inhibitor Affecting Autophagy and Cellular Differentiation

Thermal proteome profiling identifies PIP4K2A and ZADH2 as off‐targets of Polo‐like kinase 1 inhibitor volasertib

Conserved RNA Binding Activity of Phosphatidyl Inositol 5-Phosphate 4-Kinase (PIP4K2A)

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