Urolithin A, a Novel Natural Compound to Target PI3K/AKT/mTOR Pathway in Pancreatic Cancer

Totiger, Tulasigeri M.; Srinivasan, Supriya; Jala, Venkatakrishna R.; Lamichhane, Purushottam; Dosch, Austin R.; Gaidarski, Alexander A.; Joshi, Chandrashekhar G.; Rangappa, Shobith; Castellanos, Jason; Vemula, Praveen Kumar; Chen, Xi; Kwon, Deukwoo; Kashikar, Nilesh; VanSaun, Michael N.; Merchant, Nipun B.; Nagathihalli, Nagaraj S.

doi:10.1158/1535-7163.mct-18-0464

Cited by 72 publications

(57 citation statements)

References 46 publications

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“…Inhibitors of PI3K reduced tumor burden through limiting recruitment of immunosuppressive components including MDSCs and Treg cells in tumors (11,37,38). In this study, we revealed that Pik3ip1, a critical regulator of PI3K, serves as an essential rheostat for T-cell-mediated immunity, which sets the threshold for T-cell responses under homeostatic conditions and neoantigen exposure, especially tumor antigen stimulation.…”

Section: Discussionmentioning

confidence: 74%

Pik3ip1 Is a Negative Immune Regulator that Inhibits Antitumor T-Cell Immunity

Chen

Wang

et al. 2019

Clinical Cancer Research

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Purpose: Multiple negative regulators restrict the ability of T cells to attack tumors. This work demonstrates the role of PI3Kinteracting protein 1 (Pik3ip1) in restraining T-cell responses and antitumor immunity. Experimental Design: An anti-Pik3ip1 mAb was generated to identify the Pik3ip1 expression pattern of hematopoietic cells. Pik3ip1 À/À mice and a Pik3ip1 fusion protein were generated to investigate the effect of Pik3ip1 on T-cellmediated antitumor immunity in MC38 and B16-F10 tumor models. Immunoblotting and confocal microscopy were used to identify inhibitory effects of Pik3ip1 on T-cell receptor (TCR) signaling. Pik3ip1 expression was quantified, and its impact on T-cell function in human tumors was measured. Results: We demonstrated that Pik3ip1 was predominantly expressed on T cells and served as an essential rheostat for T-cell-mediated immunity. A Pik3ip1 genetic deficiency led to enhanced T-cell responsiveness upon immunization with a neoantigen. Pik3ip1 À/À mice exhibited a marked increase in antitumor immunity and were resistant to tumor growth. Furthermore, Pik3ip1 extracellular domain fusion protein enhanced MC38 tumor growth was observed. Mechanistically, we found that Pik3ip1 inhibited TCR signaling by mediating the degradation of SLP76 through Pik3ip1 oligomerization via its extracellular region. Consistent with the results from the mouse models, PIK3IP1 expression correlated with T-cell dysfunction in human tumors. Conclusions: Our data reveal a critical role for Pik3ip1 as a novel inhibitory immune regulator of T-cell responses and provide a potential molecular target for cancer immunotherapy.

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Section: Discussionmentioning

confidence: 74%

Pik3ip1 Is a Negative Immune Regulator that Inhibits Antitumor T-Cell Immunity

Chen

Wang

et al. 2019

Clinical Cancer Research

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“…Thus, it is plausible that there is a close link between the anti-cancer effects of urolithins and AHR antagonism in humans. However, other mechanisms for urolithin-mediated anti-cancer effects have been proposed [64], such as PI3K/AKT/mTOR [65] and AR receptor [66]. Further in vivo studies are certainly required for assessing the ability of urolithins to control human tumor growth, and the role of AHR in mediating these effects.…”

Section: Discussionmentioning

confidence: 99%

Urolithin A Is a Dietary Microbiota-Derived Human Aryl Hydrocarbon Receptor Antagonist

et al. 2018

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Urolithins (e.g., UroA and B) are gut microbiota-derived metabolites of the natural polyphenol ellagic acid. Urolithins are associated with various health benefits, including attenuation of inflammatory signaling, anti-cancer effects and repression of lipid accumulation. The molecular mechanisms underlying the beneficial effects of urolithins remain unclear. We hypothesize that some of the human health benefits of urolithins are mediated through the aryl hydrocarbon receptor (AHR). Utilizing a cell-based reporter system, we tested urolithins for the capacity to modulate AHR activity. Cytochrome P450 1A1 (CYP1A1) mRNA levels were assessed by real-time quantitative polymerase chain reaction. Competitive ligand binding assays were performed to determine whether UroA is a direct ligand for the AHR. Subcellular AHR protein levels were examined utilizing immunoblotting analysis. AHR expression was repressed in Caco-2 cells by siRNA transfection to investigate AHR-dependency. UroA and B were able to antagonize 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced AHR-mediated transcriptional activity. Furthermore, UroA and B attenuated TCDD-mediated stimulation of CYP1A1 mRNA levels. In addition, competitive ligand binding assays characterized UroA as a direct AHR ligand. Consistent with other AHR antagonists, UroA failed to induce AHR retention in the nucleus. AHR is necessary for UroA-mediated attenuation of cytokine-induced interleukin 6 (IL6) and prostaglandin-endoperoxide synthase 2 (PTGS2) expression in Caco-2 cells. Here we identified UroA as the first dietary-derived human selective AHR antagonist produced by the gut microbiota through multi-step metabolism. Furthermore, previously reported anti-inflammatory activity of UroA may at least in part be mediated through AHR.

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“…The mechanism of the anticancer action of UA through the inhibition of AKT and p70S6K phosphorylation, reduction of proliferation, and enhancement of cellular apoptosis has been confirmed in both xenograft and transgenic mouse models of pancreatic cancer. Additionally, UA treatment has reprogrammed the tumor microenvironment, as evidenced by reduced levels of infiltrating immunosuppressive cell populations such as myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T-cells thus inhibiting tumor growth resulting in enhanced survival[ 58 ].…”

Section: Othersmentioning

confidence: 99%

Potential of the ellagic acid-derived gut microbiota metabolite – Urolithin A in gastrointestinal protection

Kujawska

Jodynis‐Liebert

2020

WJG

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Urolithin A (UA) is a metabolic compound generated during the biotransformation of ellagitannins by the intestinal bacteria. The physiologically relevant micromolar concentrations of UA, achieved in the plasma and gastrointestinal tract (GI) after consumption of its dietary precursors, have been revealed to offer GI protection. The health benefit has been demonstrated to be principally related to anticancer and anti-inflammatory effects. UA has been shown to possess the capability to regulate multiple tumor and inflammatory signaling pathways and to modulate enzyme activity, including those involved in carcinogen biotransformation and antioxidant defense. The purpose of this review is to gather evidence from both in vitro and in vivo studies showing the potential of UA in GI protection alongside suggested mechanisms by which UA can protect against cancer and inflammatory diseases of the digestive tract. The data presented herein, covering both studies on the pure compound and in vivo generated UA form its natural precursor, support the potential of this metabolite in treatment interventions against GI ailments.

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Urolithin A, a Novel Natural Compound to Target PI3K/AKT/mTOR Pathway in Pancreatic Cancer

Cited by 72 publications

References 46 publications

Pik3ip1 Is a Negative Immune Regulator that Inhibits Antitumor T-Cell Immunity

Pik3ip1 Is a Negative Immune Regulator that Inhibits Antitumor T-Cell Immunity

Urolithin A Is a Dietary Microbiota-Derived Human Aryl Hydrocarbon Receptor Antagonist

Potential of the ellagic acid-derived gut microbiota metabolite – Urolithin A in gastrointestinal protection

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