Ikarugamycin: A Natural Product Inhibitor of Clathrin‐Mediated Endocytosis

Elkin, Sarah R.; Oswald, Nathaniel W.; Reed, Dana Kim; Mettlen, Marcel; MacMillan, John B.; Schmid, Sandra L.

doi:10.1111/tra.12425

Cited by 68 publications

(53 citation statements)

References 30 publications

(36 reference statements)

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“…Notably, IKA has been characterized as an inhibitor of clathrin-mediated endocytosis in several cancer cell lines. 18 Importantly, macropinocytosis is a crucial biological mechanism that provides the cell with amino acids, including glutamine, which aid in driving tumorigenic metabolism in PDAC. 42 In addition, IKA inhibits cholesteryl ester accumulation by specifically inhibiting the uptake of oxidized low-density lipoprotein in macrophage 774.…”

Section: Discussionmentioning

confidence: 99%

“…14 The PTMs are structurally, biosynthetically, and pharmacologically unique natural products. 15 A broad variety of biological activities of IKA has been reported, such as immune regulation, 16 cytotoxic properties, 17,18 antitumor effects and other pharmacological effects. 19,20 Previously, we screened compounds 1, 2, and 3 for their antitumor activities against pancreatic cancer in vitro.…”

Section: Introductionmentioning

confidence: 99%

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Ikarugamycin inhibits pancreatic cancer cell glycolysis by targeting hexokinase 2

Jiang

Dong

et al. 2020

FASEB j.

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Mangrove‐derived actinobacteria strains are well‐known for producing novel secondary metabolites. The polycyclic tetramate macrolactam (PTM), ikarugamycin (IKA) isolated from Streptomyces xiamenensis 318, exhibits antiproliferative activities against pancreatic ductal adenocarcinoma (PDAC) in vitro. However, the protein target for bioactive IKA is unclear. In this study, whole transcriptome‐based profiling revealed that the glycolysis pathway is significantly affected by IKA. Metabolomic studies demonstrated that IKA treatment induces a significant drop in glucose‐6‐phosphate and a slight increase in intracellular glucose level. Analysis of glucose consumption, lactate production, and the extracellular acidification rate confirmed the inhibitory role of IKA on the glycolytic flux in PDAC cells. Surface plasmon resonance (SPR) experiments and docking studies identified the key enzyme of glycolysis, hexokinase 2 (HK2), as a molecular target of IKA. Moreover, IKA reduced tumor size without overt cytotoxicity in mice with PDAC xenografts and increased chemotherapy response to gemcitabine in PDAC cells in vitro. Taken together, IKA can block glycolysis in pancreatic cancer by targeting HK2, which may be a potential drug candidate for PDAC treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ikarugamycin inhibits pancreatic cancer cell glycolysis by targeting hexokinase 2

Jiang

Dong

et al. 2020

FASEB j.

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“…To block IFNAR at the plasma membrane, we used ikarugamycin (Ika), a recently characterized natural product inhibitor of clathrin-mediated endocytosis (36).…”

Section: Ifnar1 Interaction With Hrs Relieves Stam Inhibition Of Tyk2mentioning

confidence: 99%

STAM Interaction with Hrs Controls JAK/STAT Activation by Interferon-α at the Early Endosome

Zanin

Blouin

et al. 2019

Preprint

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Activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway by type I interferons (IFN) requires clathrin-dependent endocytosis of the IFN-α/β receptor (IFNAR). The molecular machinery that brings about the selective activation of IFN-α/β-induced JAK/STAT signaling on endosomes remains unknown. Here we show that the constitutive association of STAM with IFNAR1 and the TYK2 Janus kinase at the plasma membrane prevents the activation of TYK2 by type I IFNs. IFN-α stimulated endocytosis leads to the interaction of IFNAR1 with Hrs on early endosomes, which then relieves TYK2 inhibition by STAM and thereby allows for TYK2 and IFNAR signaling. In contrast, IFN-β stimulation results in sorting of IFNAR to a distinct endosomal subdomain where the receptor is activated independently from Hrs. Our results identify the molecular machinery that controls the spatiotemporal activation of TYK2 and establish the central role of endosomal sorting in the differential regulation of JAK/STAT signaling by IFN-α and IFN-β.

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“…Studies of fluid-phase endocytosis in plants have primarily relied on the use of ikarugamycin (IKA) to distinguish between CME and CIE uptake of extracellular markers. IKA is a natural product that has been utilized as a CME inhibitor in plants and animals, although its mode of action remains to be determined (Elkin et al, 2016). Accumulation of fluorescent glucose in the endomembrane system of BY-2 protoplasts , as well as the internalization of charged nanogold particles targeted to the degradative vacuole into tobacco pollen tubes, is insensitive to IKA (Moscatelli et al, 2007), suggesting that the uptake of these reporters is mediated through the CIE mechanism(s).…”

Section: Ciementioning

confidence: 99%