Allosteric Regulation of Phosphatidylinositol 4-Kinase III Beta by an Antipicornavirus Compound MDL-860

Arita, Minetaro; Dobrikov, Georgi M.; Pürstinger, Gerhard; Galabov, Angel S.

doi:10.1021/acsinfecdis.7b00053

Cited by 18 publications

(15 citation statements)

References 60 publications

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“…PI4KIIIβ antagonist-tolerant cells relied on PI4KII-α for prosurvival effector protein secretion and cell viability, indicating that drug tolerance resulted from an alternative enzymatic source of Golgi-resident PI4P synthesis. The findings presented here recapitulate evidence from EGFR-, BCR/ABL-, and BRAF-mutant malignancies that resistance to targeted therapies develops through genetic and epigenetic events that restore mutant oncoprotein activity and build on the finding that mutant oncoproteins maintain cancer cell viability by regulating lipid metabolism (18)(19)(20)(21)(22). In contrast to Golgi-resident PI4P, which drives the biogenesis of secretory vesicles carrying prosurvival cargos, PI-3,4,5-phosphate generated by PI3K activates prosurvival signaling pathways in PIK3CA-mutant cancer cells, whereas fatty acid uptake, retention, and beta-oxidation driven by acyl-CoA synthetase long chain 3 maintain the survival of KRAS-mutant cancer cells (19,20).…”

Section: Discussionsupporting

confidence: 71%

Addiction to Golgi-resident PI4P synthesis in chromosome 1q21.3–amplified lung adenocarcinoma cells

Shi

Tan

Liu

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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A chromosome 1q21.3 region that is frequently amplified in diverse cancer types encodes phosphatidylinositol (PI)-4 kinase IIIβ (PI4KIIIβ), a key regulator of secretory vesicle biogenesis and trafficking. Chromosome 1q21.3–amplified lung adenocarcinoma (1q-LUAD) cells rely on PI4KIIIβ for Golgi-resident PI-4-phosphate (PI4P) synthesis, prosurvival effector protein secretion, and cell viability. Here, we show that 1q-LUAD cells subjected to prolonged PI4KIIIβ antagonist treatment acquire tolerance by activating an miR-218-5p–dependent competing endogenous RNA network that up-regulates PI4KIIα, which provides an alternative source of Golgi-resident PI4P that maintains prosurvival effector protein secretion and cell viability. These findings demonstrate an addiction to Golgi-resident PI4P synthesis in a genetically defined subset of cancers.

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Section: Discussionsupporting

confidence: 71%

Addiction to Golgi-resident PI4P synthesis in chromosome 1q21.3–amplified lung adenocarcinoma cells

Shi

Tan

Liu

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…It is probably too early yet to say definitively that this is a feasible therapeutic route or even to know how to identify such phenotypes in a clinical setting. However, several small molecule inhibitors of PI4KIIIβ have already been identified as efficacious anti-viral (102)(103)(104)(105)(106)(107) or anti-apicomplexa drugs useful for treating malaria (108)(109)(110)(111)(112) and cryptosporidiosis (113). The use of these compounds to combat infectious diseases is beyond the scope of this review but there appears to be at least some potential for repurposing these existing molecules (106,114,115) as anti-cancer drugs.…”

Section: The Golgi Complex As a Phosphoinositide-dependent Traffickinmentioning

confidence: 99%

The Great Escape: how phosphatidylinositol 4-kinases and PI4P promote vesicle exit from the Golgi (and drive cancer)

Waugh

2019

Biochemical Journal

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Phosphatidylinositol 4-phosphate (PI4P) is a membrane glycerophospholipid and a major regulator of the characteristic appearance of the Golgi complex as well as its vesicular trafficking, signalling and metabolic functions. Phosphatidylinositol 4-kinases, and in particular the PI4KIIIβ isoform, act in concert with PI4P to recruit macromolecular complexes to initiate the biogenesis of trafficking vesicles for several Golgi exit routes. Dysregulation of Golgi PI4P metabolism and the PI4P protein interactome features in many cancers and is often associated with tumour progression and a poor prognosis. Increased expression of PI4P-binding proteins, such as GOLPH3 or PITPNC1, induces a malignant secretory phenotype and the release of proteins that can remodel the extracellular matrix, promote angiogenesis and enhance cell motility. Aberrant Golgi PI4P metabolism can also result in the impaired post-translational modification of proteins required for focal adhesion formation and cell–matrix interactions, thereby potentiating the development of aggressive metastatic and invasive tumours. Altered expression of the Golgi-targeted PI 4-kinases, PI4KIIIβ, PI4KIIα and PI4KIIβ, or the PI4P phosphate Sac1, can also modulate oncogenic signalling through effects on TGN-endosomal trafficking. A Golgi trafficking role for a PIP 5-kinase has been recently described, which indicates that PI4P is not the only functionally important phosphoinositide at this subcellular location. This review charts new developments in our understanding of phosphatidylinositol 4-kinase function at the Golgi and how PI4P-dependent trafficking can be deregulated in malignant disease.

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“…It is one of the few drug candidates that has shown effective antiviral infection in in vivo experiments. MDL-860 treatment causes PI4KB covalent modification and irreversible inactivation (Arita et al, 2017). In addition, another major enviroxime-like compounds, such as pachypodol (Ro 09-0179), oxoglaucine, GW5074, BF-738735, and T-00127-HEV1, can also inhibit PI4KB to hamper the formation of ROs (Arita et al, 2009(Arita et al, , 2011(Arita et al, , 2015MacLeod et al, 2013;van der Schaar et al, 2013;Ford Siltz et al, 2014;Bauer et al, 2017; Table 2).…”

Section: Inhibitors Target Pi4kbmentioning

confidence: 99%

Enterovirus Replication Organelles and Inhibitors of Their Formation

Wang

Cheng

et al. 2020

Front. Microbiol.

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Enteroviral replication reorganizes the cellular membrane. Upon infection, viral proteins and hijacked host factors generate unique structures called replication organelles (ROs) to replicate their viral genomes. ROs promote efficient viral genome replication, coordinate the steps of the viral replication cycle, and protect viral RNA from host immune responses. More recent researches have focused on the ultrastructure structures, formation mechanism, and functions in the virus life cycle of ROs. Dynamic model of enterovirus ROs structure is proposed, and the secretory pathway, the autophagy pathway, and lipid metabolism are found to be associated in the formation of ROs. With deeper understanding of ROs, some compounds have been found to show inhibitory effects on viral replication by targeting key proteins in the process of ROs formation. Here, we review the recent findings concerning the role, morphology, biogenesis, formation mechanism, and inhibitors of enterovirus ROs.

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Allosteric Regulation of Phosphatidylinositol 4-Kinase III Beta by an Antipicornavirus Compound MDL-860

Cited by 18 publications

References 60 publications

Addiction to Golgi-resident PI4P synthesis in chromosome 1q21.3–amplified lung adenocarcinoma cells

Addiction to Golgi-resident PI4P synthesis in chromosome 1q21.3–amplified lung adenocarcinoma cells

The Great Escape: how phosphatidylinositol 4-kinases and PI4P promote vesicle exit from the Golgi (and drive cancer)

Enterovirus Replication Organelles and Inhibitors of Their Formation

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