LAMTOR/Ragulator regulates lipid metabolism in macrophages and foam cell differentiation

Lamberti, Giorgia; Smet, Cedric H. De; Angelova, Mihaela; Kremser, Leopold; Taub, Nicole; Herrmann, Caroline; Hess, Michael W.; Rainer, Johannes Michael; Tancevski, Ivan; Schweigreiter, Rüdiger; Kofler, Reinhard; Schmiedinger, Thomas; Vietor, Ilja; Trajanoski, Zlatko; Ejsing, Christer S.; Lindner, Herbert; Huber, Lukas A.; Stasyk, Taras

doi:10.1002/1873-3468.13579

Cited by 9 publications

(7 citation statements)

References 49 publications

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“…LAMTOR4 is part of the Rag complex, a scaffold protein complex comprised of LAMTOR subunits 1–5 that senses amino acids and lips and integrates growth factor signaling [ 44 ]. This “Ragulator” complex also controls the activity of the mTOR complex 1 (mTORC1) on the lysosome [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Distinct Synaptic Vesicle Proteomic Signatures Associated with Pre- and Post-Natal Oxycodone-Exposure

Odegaard

Gallegos

Koul

et al. 2022

Cells

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The current opioid crisis, which has ravaged all segments of society, continues to pose a rising public health concern. Importantly, dependency on prescription opioids such as oxycodone (oxy) during and after pregnancy can significantly impact the overall brain development of the exposed offspring, especially at the synapse. A significant knowledge gap that remains is identifying distinct synaptic signatures associated with these exposed offspring. Accordingly, the overall goal of this current study was to identify distinct synaptic vesicle (SV) proteins as signatures for offspring exposed to oxy in utero (IUO) and postnatally (PNO). Using a preclinical animal model that imitates oxycodone exposure in utero (IUO) and postnatally (PNO), we used a quantitative mass spectrometry-based proteomics platform to examine changes in the synaptic vesicle proteome on post-natal day 14 (P14) IUO and PNO offspring. We identified MEGF8, associated with carpenter syndrome, to be downregulated in the IUO offspring while LAMTOR4, associated with the regulator complex involved in lysosomal signaling and trafficking, was found to be upregulated in the PNO groups, respectively. Their respective differential expression was further validated by Western blot. In summary, our current study shows exposure to oxy in utero and postnatally can impact the SV proteome in the exposed offspring and the identification of these distinct SV signatures could further pave the way to further elucidate their downstream mechanisms including developing them as potential therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Distinct Synaptic Vesicle Proteomic Signatures Associated with Pre- and Post-Natal Oxycodone-Exposure

Odegaard

Gallegos

Koul

et al. 2022

Cells

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“…These included genes specifically annotated for cholesterol uptake and trafficking, including scavenger receptors like SCP2 and SCARB1, endosome associated proteins such as STARD3/NL, NPC1/2, and transcription factor SREBF2(21–25). Additional upregulated genes, COMMD1, WASH1, ANXA2, and LAMTOR1, function in cholesterol uptake and trafficking as well as other cellular processes (26–29). Increased expression of genes related to cholesterol uptake and trafficking in activated human T cells supports translatability of these findings.…”

Section: Resultsmentioning

confidence: 99%

Predicting efficacy of immunotherapy in mice with triple negative breast cancer using a cholesterol PET radiotracer

Ciavattone,

Guan,

Farfel

et al. 2023

Preprint

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Predicting the response to cancer immunotherapy remains an unmet challenge in triple-negative breast cancer (TNBC) and other malignancies. T cells, the major target of current checkpoint inhibitor immunotherapies, accumulate cholesterol during activation to support proliferation and signaling. The requirement of cholesterol for anti-tumor functions of T cells led us to hypothesize that quantifying cellular accumulation of this molecule could distinguish successful from ineffective checkpoint immunotherapy. To analyze accumulation of cholesterol by T cells in the immune microenvironment of breast cancer, we leveraged a novel positron emission tomography (PET) radiotracer, FNP-59. FNP-59 is an analog of cholesterol that our group has validated as an imaging biomarker for cholesterol uptake in pre-clinical models and initial human studies. In immunocompetent mouse models of TNBC, we found that elevated uptake of exogenous labeled cholesterol analogs functions as a marker for T cell activation. When comparing immune checkpoint inhibitor (ICI)-responsive EO771 tumors to non-responsive AT-3 tumors, we found significantly higher uptake of a fluorescent cholesterol analog in T cells of the ICI-responsive tumors both in vitro and in vivo. Using the FNP-59 radiotracer, we discovered that accumulation of cholesterol by T cells increased further in ICI-responding tumors that received ant-PD-1 checkpoint immunotherapy. We verified these data by mining single cell sequencing data from patients with TNBC. Patients with tumors containing cycling T cells showed gene expression signatures of cholesterol uptake and trafficking. These results suggest that uptake of exogenous cholesterol analogs by tumor-infiltrating T cells predict T cell activation and success of ICI therapy.

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“…LAMTOR is a scaffold protein complex that senses nutrients such as amino acids and lipids while integrating growth factor signaling [72]. LAMTOR1 functions as an anchor for the remaining LAMTOR subunits [73][74][75][76][77]. LAM-TOR was also reported to activate mTORC1 signaling [78].…”

Section: Discussionmentioning

confidence: 99%

Modulation of AMPK Significantly Alters Uveal Melanoma Tumor Cell Viability

Deliktas,

Gedik,

Koc

et al. 2023

Ophthalmic Res

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Introduction: Uveal melanoma (UM) responds poorly to targeted therapies or immune checkpoint inhibitors. Adenosine monophosphate-activated protein kinase (AMPK) is a pivotal serine/threonine protein kinase that coordinates vital processes such as cell growth. Targeting AMPK pathway, which represents a critical mechanism mediating the survival of UM cells, may prove to be a novel treatment strategy for UM. We aimed to demonstrate the effects of AMPK modulation on UM cells. Methods: In silico analyses were performed to compare UM and normal melanocyte cells via Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA). The effects of AMPK modulation on cell viability and proliferation in UM cell lines with different molecular profiles (i.e., 92-1, MP46, OMM2.5, and Mel270) were investigated via XTT cell viability and proliferation assays after treating the cells with varying concentrations of A-769662 (AMPK activator) or dorsomorphin (AMPK inhibitor). Results: KEGG/GSEA studies demonstrated that genes implicated in the AMPK signaling pathway were differentially regulated in UM. Gene sets comprising genes involved in AMPK signaling and genes involved in energy-dependent regulation of mammalian target of rapamycin by liver kinase B1-AMPK were downregulated in UM. We observed gradual decreases in the numbers of viable UM cells as the concentration of A-769662 treatment increased. All UM cells demonstrated statistically significant decreases in cell viability when treated with 200 µ<sc>m</sc> A-769662. Moreover, the effects of AMPK inhibition on UM cells were potent, since low doses of dorsomorphin treatment resulted in significant decreases in viabilities of UM cells. The half maximal inhibitory concentration (IC50) values confirmed the potency of dorsomorphin treatment against UM in vitro. Conclusion: AMPK may act like a friend or a foe in cancer depending on the context. As such, the current study contributes to the literature in determining the effects of therapeutic strategies targeting AMPK in several UM cells. We propose a new perspective in the treatment of UM. Targeting AMPK pathway may open up new avenues in developing novel therapeutic approaches to improve overall survival in UM.

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LAMTOR/Ragulator regulates lipid metabolism in macrophages and foam cell differentiation

Cited by 9 publications

References 49 publications

Distinct Synaptic Vesicle Proteomic Signatures Associated with Pre- and Post-Natal Oxycodone-Exposure

Distinct Synaptic Vesicle Proteomic Signatures Associated with Pre- and Post-Natal Oxycodone-Exposure

Predicting efficacy of immunotherapy in mice with triple negative breast cancer using a cholesterol PET radiotracer

Modulation of AMPK Significantly Alters Uveal Melanoma Tumor Cell Viability

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