ArticlePloS one2013
RasGRPs are targets of the anti-cancer agent ingenol-3-angelate.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 20 citations in OpenAlex.
- Dysregulation of RasGRP1 in rheumatoid arthritis and modulation of RasGRP3 as a biomarker of TNFα inhibitors.Arthritis research & therapy · 2015Trial
- Ingenol-3-Angelate Enhances the B Cell Inhibitory Potential of Mesenchymal Stem Cells, Leading to Marked Alleviation of Lupus Symptoms in MRL.International journal of molecular sciences · 2024Article
- Regulation of the Ras-Related Signaling Pathway by Small Molecules Containing an Indole Core Scaffold: A Potential Antitumor Therapy.Frontiers in pharmacology · 2020Review
- Mechanism of inhibition of Shiga-toxigenicCell death discovery · 2018Article
- Anticancer activity of the protein kinase C modulator HMI-1a3 in 2D and 3D cell culture models of androgen-responsive and androgen-unresponsive prostate cancer.FEBS open bio · 2018Article
- Oncolytic Reactivation of KSHV as a Therapeutic Approach for Primary Effusion Lymphoma.Molecular cancer therapeutics · 2017Article
- Exploring the influence of indololactone structure on selectivity for binding to the C1 domains of PKCα, PKCε, and RasGRP.Bioorganic & medicinal chemistry · 2017Article
- Increasing the synthesis of bioactive abietane diterpenes in Salvia sclarea hairy roots by elicited transcriptional reprogramming.Plant cell reports · 2017Article
- C-H Oxidation of Ingenanes Enables Potent and Selective Protein Kinase C Isoform Activation.Angewandte Chemie (International ed. in English) · 2015Article
- Article
- Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP.Bioorganic & medicinal chemistry · 2014Article
- Intra-lesional injection of the novel PKC activator EBC-46 rapidly ablates tumors in mouse models.PloS one · 2014Article
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
Abstract
Ingenol-3-angelate (I3A) is a non-tumor promoting phorbol ester-like compound identified in the sap of Euphoria peplus. Similar to tumor promoting phorbol esters, I3A is a diacylglycerol (DAG) analogue that binds with high affinity to the C1 domains of PKCs, recruits PKCs to cellular membranes and promotes enzyme activation. Numerous anti-cancer activities have been attributed to I3A and ascribed to I3A's effects on PKCs. We show here that I3A also binds to and activates members of the RasGRP family of Ras activators leading to robust elevation of Ras-GTP and engagement of the Raf-Mek-Erk kinase cascade. In response to I3A, recombinant proteins consisting of GFP fused separately to full-length RasGRP1 and RasGRP3 were rapidly recruited to cell membranes, consistent with direct binding of the compound to RasGRP's C1 domain. In the case of RasGRP3, IA3 treatment led to positive regulatory phosphorylation on T133 and activation of the candidate regulatory kinase PKCδ. I3A treatment of select B non-Hodgkin's lymphoma cell lines resulted in quantitative and qualitative changes in Bcl-2 family member proteins and induction of apoptosis, as previously demonstrated with the DAG analogue bryostatin 1 and its synthetic analogue pico. Our results offer further insights into the anticancer properties of I3A, support the idea that RasGRPs represent potential cancer therapeutic targets along with PKC, and expand the known range of ligands for RasGRP regulation.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.