Lithocholic acid inhibits gallbladder cancer proliferation through interfering glutaminase-mediated glutamine metabolism

Li, Weijian; Wang, Zeyu; Lin, Rongfu; Huang, Shuai; Miao, Huijie; Zou, Lu; Liu, Ke; Cui, Xuya; Wang, Ziyi; Zhang, Yijian; Jiang, Chengkai; Qiu, Shimei; Ma, Jiyao; Wu, Wenzhi; Liu, Yingbin

doi:10.1016/j.bcp.2022.115253

Cited by 16 publications

(13 citation statements)

References 45 publications

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“…CDCA has procarcinogenic features [58], CA and UDCA have antineoplastic features [27,65], and DCA has mixed effects [25,55,58]). LCA possesses antineoplastic features in neoplasias other than pancreatic adenocarcinoma, including breast cancer [7,9,47], neuroblastoma [41], prostate cancer [42,43], liver cancer [46], gallbladder cancer [45], and nephroblastoma [44]. These effects are selective for neoplasias, as LCA did not affect primary, non-transformed cells [7].…”

Section: Discussionmentioning

confidence: 99%

“…Originally, LCA was considered procarcinogenic [38][39][40]; however, recent studies showed that LCA also has anti-tumor effects. LCA has antineoplastic effects in a variety of tumors, including neuroblastoma [41], prostate cancer [42,43], nephroblastoma [44], gallbladder cancer [45], liver cancer [46], and breast cancer [7,9,47]. Due to the widespread antineoplastic effects of LCA, we investigated its effects in pancreatic adenocarcinoma.…”

Section: Introductionmentioning

confidence: 99%

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The bacterial metabolite, lithocholic acid, has antineoplastic effects in pancreatic adenocarcinoma

Mikó,

Schwarcz,

Kovács

et al. 2024

Preprint

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Lithocholic acid (LCA) is a secondary bile acid. LCA enters the circulation after bacterial synthesis in the gastrointestinal tract, reaches distantly located cancer cells, and influences their behavior. LCA was considered carcinogenic, but recent studies demonstrated that LCA has antitumor effects. We assessed the possible role of LCA in pancreatic adenocarcinoma. At the serum reference concentration, LCA induced a multi-pronged antineoplastic program in pancreatic adenocarcinoma cells. LCA inhibited cancer cell proliferation and induced mesenchymal-to-epithelial (MET) transition that reduced cell invasion capacity. LCA induced oxidative/nitrosative stress by decreasing the expression of nuclear factor, erythroid 2-like 2 (NRF2) and inducing inducible nitric oxide synthase (iNOS). The oxidative/nitrosative stress increased protein nitration and lipid peroxidation. Suppression of oxidative stress by glutathione (GSH) or pegylated catalase (pegCAT) blunted LCA-induced MET. Antioxidant genes were overexpressed in pancreatic adenocarcinoma and decreased antioxidant levels correlated with better survival of pancreatic adenocarcinoma patients. Furthermore, LCA treatment decreased the proportions of cancer stem cells. Finally, LCA induced total and ATP-linked mitochondrial oxidation and fatty acid oxidation. LCA exerted effects through the farnesoid X receptor (FXR), vitamin D receptor (VDR), and constitutive androstane receptor (CAR). LCA did not interfere with cytostatic agents used in the chemotherapy of pancreatic adenocarcinoma. Taken together, LCA is a non-toxic compound and has antineoplastic effects in pancreatic adenocarcinoma.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The bacterial metabolite, lithocholic acid, has antineoplastic effects in pancreatic adenocarcinoma

Mikó,

Schwarcz,

Kovács

et al. 2024

Preprint

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“…Blocking of Gln metabolism was assumed to inhibit the material replenishment of the TCA cycle, thus reducing NADPH production. [40] The NADP + /NADPH ratio strongly increased in the IRCB and IRCB@M groups, indicating the efficiency of GLS inhibition (Figure 3B). Moreover, Gln metabolism has an irreplaceable role in the GSH and GSSG system balance.…”

Section: In Vitro Destruction Of the Cell Reduction Systemmentioning

confidence: 93%

Improved Photodynamic Therapy Based on Glutaminase Blockage via Tumor Membrane Coated CB‐839/IR‐780 Nanoparticles

Li,

et al. 2023

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Photodynamic therapy (PDT) has promising applications. However, the lethal function of reactive oxygen species (ROS) produced during PDT is typically limited. This restriction is induced by oxygen shortage in the tumor microenvironment due to tumor cell hypermetabolism and reductive chemicals overexpression in tumor tissues. Glutamine (Gln) metabolism is crucial for malignancy development and is closely associated with redox. Herein, a novel nanoparticle (NP) named IRCB@M is constructed to boost PDT through dual effects. This NP simultaneously blocks aerobic respiration and inhibits cellular reduced substances by blocking the Gln metabolic pathway. Within the nanocomplex, a photosensitizer (IR‐780) and a glutaminase inhibitor (CB‐839) are self‐assembled and then encapsulated by cancer cell membranes for homologous targeting. The Gln metabolism intervention relieves hypoxia and decreases the levels of nicotinamide adenine dinucleotide phosphate (NADPH) as well as reduced glutathione (GSH) in vitro and in vivo, which are the dual amplification effects on the IR‐780‐mediated lethal PDT. The antitumor effects against gastric cancer are ultimately evoked in vivo, thus offering a novel concept for enhancing PDT and other ROS‐dependent therapeutic approaches.

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“…LCA, DCA and CDCA are confirmed to be intimately related to the development of GBC, acting as tumor suppressors in GBC. First, serum LCA is significantly decreased in patients with GBC, which is associated with poor clinical outcomes ( Li et al., 2022 ). The anti-cancer mechanism of LCA in GBC can be explained from two aspects.…”

Section: Bacteria In Gbc Pathogenesismentioning

confidence: 99%

“…The anti-cancer mechanism of LCA in GBC can be explained from two aspects. On the one hand, LCA induces cellular ferroptosis and inhibits GBC cell proliferation by downregulating glutaminase-mediated glutamine metabolism ( Figure 2A ) ( Li et al., 2022 ). On the other hand, LCA can also produce effective antibacterial effects against Gram-positive multidrug-resistant pathogens, including Clostridioides difficile and Enterococcus faecalis , which in turn mediates anti-cancer effect ( Sato et al., 2021 ).…”

Section: Bacteria In Gbc Pathogenesismentioning

confidence: 99%

The footprint of gut microbiota in gallbladder cancer: a mechanistic review

Liu,

Li,

Chen

et al. 2024

Front. Cell. Infect. Microbiol.

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Gallbladder cancer (GBC) is the most common malignant tumor of the biliary system with the worst prognosis. Even after radical surgery, the majority of patients with GBC have difficulty achieving a clinical cure. The risk of tumor recurrence remains more than 65%, and the overall 5-year survival rate is less than 5%. The gut microbiota refers to a variety of microorganisms living in the human intestine, including bacteria, viruses and fungi, which profoundly affect the host state of general health, disease and even cancer. Over the past few decades, substantial evidence has supported that gut microbiota plays a critical role in promoting the progression of GBC. In this review, we summarize the functions, molecular mechanisms and recent advances of the intestinal microbiota in GBC. We focus on the driving role of bacteria in pivotal pathways, such as virulence factors, metabolites derived from intestinal bacteria, chronic inflammatory responses and ecological niche remodeling. Additionally, we emphasize the high level of correlation between viruses and fungi, especially EBV and Candida spp., with GBC. In general, this review not only provides a solid theoretical basis for the close relationship between gut microbiota and GBC but also highlights more potential research directions for further research in the future.

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Lithocholic acid inhibits gallbladder cancer proliferation through interfering glutaminase-mediated glutamine metabolism

Cited by 16 publications

References 45 publications

The bacterial metabolite, lithocholic acid, has antineoplastic effects in pancreatic adenocarcinoma

The bacterial metabolite, lithocholic acid, has antineoplastic effects in pancreatic adenocarcinoma

Improved Photodynamic Therapy Based on Glutaminase Blockage via Tumor Membrane Coated CB‐839/IR‐780 Nanoparticles

The footprint of gut microbiota in gallbladder cancer: a mechanistic review

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