PI4KIIα is a novel regulator of tumor growth by its action on angiogenesis and HIF-1α regulation

Li, J; Lu, Yao; Zhang, Jinhua; Kang, Hua; Qin, Zhiwei; Chen, C

doi:10.1038/onc.2010.14

Cited by 53 publications

(59 citation statements)

References 40 publications

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“…Because PI4KIIa plays important roles in Golgi trafficking (14,42,43) and tumor progression (3,4,44), SMIs of PI4KIIa have potential as chemical tools for studying the biological function of PI4KIIa and breast cancer treatment (10,19,42). Here, PI-273 was screened out and identified as the most potent inhibitor of PI4KIIa activity and breast cancer cell viability.…”

Section: Discussionmentioning

confidence: 99%

“…4B), indicating that PI4KIIa is essential for the effect of PI-273 on cell viability. Because our previous works (4,17) and other studies indicated that PI4KIIa can regulate the AKT signaling pathway (3), we tested the effects of our compounds on AKT signaling. As shown in Fig.…”

Section: Pi4kiia Is Required For the Inhibitory Effect Of Pi-273mentioning

confidence: 99%

“…Recently, an increasing number of reports have identified PI4KIIa as a potential target for breast cancer therapy (3,4,(16)(17)(18)(19). We previously reported that increased PI4KIIa expression promotes tumor growth by altering the HER2/PI3-kinase (PI3K)/ERK signaling cascades (4) and that dual inhibition of EGFR and PI4KIIa represents a novel strategy to combat EGFR-dependent tumors (17). PI4KIIa is also important for the Wnt (20,21) and Akt (3) signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

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PI-273, a Substrate-Competitive, Specific Small-Molecule Inhibitor of PI4KIIα, Inhibits the Growth of Breast Cancer Cells

Gao

Zhao

et al. 2017

Cancer Research

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While phosphatidylinositol 4-kinase (PI4KIIa) has been identified as a potential target for antitumor therapy, the clinical applications of PI4KIIa are limited by a lack of specific inhibitors. Here we report the first small-molecule inhibitor (SMI) of human PI4KIIa. Docking-based and ligand-based virtual screening strategies were first employed to identify promising hits, followed by two rounds of kinase activity inhibition validation. 2-(3-(4-Chlorobenzoyl)thioureido)-4-ethyl-5-methylthiophene-3-carboxamide (PI-273) exhibited the greatest inhibitory effect on PI4KIIa kinase activity (IC 50 ¼ 0.47 mmol/L) and suppressed cell proliferation. Surface plasmon resonance and thermal shift assays indicated that PI-273 interacted directly with PI4KIIa. Kinetic analysis identified PI-273 as a reversible competitive inhibitor with respect to the substrate phosphatidylinositol (PI), which contrasted with most other PI kinase inhibitors that bind the ATP binding site. PI-273 reduced PI4P content, cell viability, and AKT signaling in wild-type MCF-7 cells, but not in PI4KIIa knockout MCF-7 cells, indicating that PI-273 is highly selective for PI4KIIa. Mutant analysis revealed a role of palmitoylation insertion in the selectivity of PI-273 for PI4KIIa. In addition, PI-273 treatment retarded cell proliferation by blocking cells in G 2 -M, inducing cell apoptosis and suppressing colony-forming ability. Importantly, PI-273 significantly inhibited MCF-7 cell-induced breast tumor growth without toxicity. PI-273 is the first substratecompetitive, subtype-specific inhibitor of PI4KIIa, the use of which will facilitate evaluations of PI4KIIa as a cancer therapeutic target. Cancer Res; 77(22); 6253-66. Ó2017 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Pi4kiia Is Required For the Inhibitory Effect Of Pi-273mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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PI-273, a Substrate-Competitive, Specific Small-Molecule Inhibitor of PI4KIIα, Inhibits the Growth of Breast Cancer Cells

Gao

Zhao

et al. 2017

Cancer Research

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“…Importantly, it brings PI4KII out of the shadow of PI3K and sheds new light on the study of PI4KII in its own rite. Future studies could be focused on the following directions: (i) Discovery of specific inhibitors based on the ADP binding pocket of PI4KII PI4KII has been proved as an oncoprotein and suppression of its expression level inhibits tumor growth [3]. Recently it was found that dual inhibition of EGFR at the protein and activity level via combinatorial blocking of PI4KII had a marked anti-tumor effect [4].…”

mentioning

confidence: 99%

Puzzle out the regulation mechanism of PI4KIIα activity

Sun

Chen

2014

Sci. China Life Sci.

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Phosphatidylinositol 4-kinase II (PI4KII), the most abundant PI4K in mammalian cells, is best known for its essential role in providing the substrate for phosphatidylinositol 3-kinase (PI3K), an important kinase for phospholipid signaling. PI4KII also plays important roles in membrane trafficking, phagocytosis and the exo-endocytic cycle of synaptic vesicles. Its dysfunction results in tumor growth, spastic paraplegia and Gaucher's disease. Therefore, PI4KII may potentially be an important drug target.The PI4K family comprises type II (55 kD PI4KII and PI4KIIβ) and type III PI4Ks (230 kD PI4KIIIand 92 kD PI4KIIIβ). Phylogenetic analysis [1] based on their sequences ( Figure 1A) reveals that PI4KIIIs are closed to PI3Ks thus belong to the PI 3/4-kinase family while PI4KIIs have more closed relationship with protein kinases (e.g., Actin fragmin kinase). This suggests that PI4KIIs should have a substrate binding pocket that is distinct from that of PI3Ks and PI4KIIIs. In addition, PI4KII contains a '-CCPCC-' motif that is palmitoylated in vivo and such palmitoylation is important for the kinase activity of PI4KII. Thus currently structural information available on PI3Ks and the well-developed specific PI3K inhibitors are not helpful for understanding the substrate binding specificity and the activity regulation of PI4KIIs.Recently, the first crystal structure in the PI4K family, the catalytic domain of human PI4KII in an ADP-bound form was solved [2], and three novel insertions of PI4KII, namely I1 (a palmitoylation insertion), I2 (an RK-rich insertion) and I3 were found in this crystal structure ( Figure 1B). These three insertions distinguish PI4KII from the structures of PI3Ks ( Figure 1C). Furthermore, a distinct nucleotide-binding pocket of PI4KII differs notably from that of PI3Ks, which well explained the insensitivity of PI4KII to PI3Ks' inhibitors. Although many crystal structures of PIKs have already been solved, the precise nature of the substrate binding pocket is still not clear. The molecular dynamics (MD) simulation approach was utilized to identify a putative PI-binding pocket that was further evaluated using mutagenesis. More importantly, the MD simulation, biochemical and mutagenesis studies revealed a novel mechanism for the regulation of PI4KII's kinase activity, in which any perturbation of the interaction between PI4KII and the membrane will affect either the nucleotide binding or PI binding and subsequently modulate the kinase activity of PI4KII.Current work [2] has provided insight into how the kinase activity of PI4KII is regulated at the molecular level. It also lays a foundation for designing specific PI4KII inhibitors and activators for future therapeutic applications. Importantly, it brings PI4KII out of the shadow of PI3K and sheds new light on the study of PI4KII in its own rite. Future studies could be focused on the following directions: (i) Discovery of specific inhibitors based on the ADP binding pocket of PI4KII PI4KII has been proved as an oncoprotein and...

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“…For example, PI4KIIa has been reported highly expressed in malignant melanoma, fibrosarcoma, bladder, thyroid, and breast cancer and its expression has been shown to promote tumor angiogenesis (46). In addition, high levels of PI4KIIIa expression are also associated with invasive and metastatic pancreatic cancer development (47).…”

Section: Discussionmentioning

confidence: 99%

The Lipid Kinase PI4KIIIβ Is Highly Expressed in Breast Tumors and Activates Akt in Cooperation with Rab11a

Morrow

Alipour

Bridges

et al. 2014

Molecular Cancer Research

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PI4KIIα is a novel regulator of tumor growth by its action on angiogenesis and HIF-1α regulation

Cited by 53 publications

References 40 publications

PI-273, a Substrate-Competitive, Specific Small-Molecule Inhibitor of PI4KIIα, Inhibits the Growth of Breast Cancer Cells

PI-273, a Substrate-Competitive, Specific Small-Molecule Inhibitor of PI4KIIα, Inhibits the Growth of Breast Cancer Cells

Puzzle out the regulation mechanism of PI4KIIα activity

The Lipid Kinase PI4KIIIβ Is Highly Expressed in Breast Tumors and Activates Akt in Cooperation with Rab11a

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