Ammonium chloride inhibits autophagy of hepatocellular carcinoma cells through SMAD2 signaling

Sun, Ranran; Luo, Yi; Li, Juan; Wang, Qiongye; Li, Jingjing; Chen, Xiaolong; Guan, Kelei; Yu, Zujiang

doi:10.1007/s13277-014-2699-x

Cited by 18 publications

(14 citation statements)

References 17 publications

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“…[39,40] These morphological changes coincided with modifications in the actin cytoskeletal architecture such as the re-organization in filamentous actin and a significant up-regulation in α-SMA and myosin IIa protein expression, after a prolonged treatment with ammonia. Furthermore, ammonia induced contraction of hHSC, indicating that ammonia strongly affects actin, which is important in maintaining HSC cell integrity and function.…”

Section: Discussionmentioning

confidence: 89%

Ammonia produces pathological changes in human hepatic stellate cells and is a target for therapy of portal hypertension

Jalan

Chiara

Vairappan

et al. 2016

Journal of Hepatology

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Section: Discussionmentioning

confidence: 89%

Ammonia produces pathological changes in human hepatic stellate cells and is a target for therapy of portal hypertension

Jalan

Chiara

Vairappan

et al. 2016

Journal of Hepatology

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“…Ammonium is a widely used molecule to alter lysosomal function, by inducing a pH raise inhibiting proteases activity56. Ammonium has even been reported to inhibit rapamycin-induced autophagy in hepatocarcinoma HepG2 cells57. However, in these cases, ammonium concentrations used are above 10 mM, thus far above the levels found in tumor xenografts101112.…”

Section: Discussionmentioning

confidence: 99%

The metabolic waste ammonium regulates mTORC2 and mTORC1 signaling

Ahmad

Delrée

Marini

2017

Sci Rep

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Two structurally and functionally distinct mammalian TOR complexes control cell growth and metabolism in physiological and pathological contexts including cancer. Upregulated glutaminolysis is part of the metabolic reprogramming occurring in cancer, providing fuels for growth but also liberating ammonium, a potent neurotoxic waste product. Here, we identify ammonium as a novel dose-dependent signal mediating rapid mTORC2 activation and further regulating mTORC1. We show that ammonium induces rapid RICTOR-dependent phosphorylation of AKT-S473, a process requiring the PI3K pathway and further involving the Src-family kinase YES1, the FAK kinase and the ITGβ1 integrin. Release of calcium from the endoplasmic reticulum store triggers rapid mTORC2 activation, similar to ammonium-induced activation, the latter being conversely prevented by calcium chelation.Moreover, in analogy to growth factors, ammonium triggers the AKT-dependent phosphoinhibition of the TSC complex and of PRAS40, two negative regulators of mTORC1. Consistent with mTORC1 stimulation, ammonium induces the inhibitory phosphorylation of 4EBP1, a negative regulator of protein biogenesis. Ammonium however dually impacts on the phosphorylation of p70S6K1 triggering a transient AKT-independent decrease in the phosphorylation of this second mTORC1 readout. Finally, we reveal ammonium as a dose-dependent stimulator of proliferation. This study underscores an mTORC2 and mTORC1 response to the so-called ammonium waste.

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“…[ 56 ] JNK-Bcl-2/Bcl-xL-Bax/Bak pathway and SMAD2 signaling have also been determined as contributors to autophagy of HCC. [ 57 58 ]…”

Section: A Utophagy-mediated C Hemoresismentioning

confidence: 99%

Autophagy in 5-Fluorouracil Therapy in Gastrointestinal Cancer

Tang

Feng

Liang

et al. 2016

Chinese Medical Journal

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Objective:5-Fluorouracil (5-FU)-based combination therapies are standard treatments for gastrointestinal cancer, where the modulation of autophagy is becoming increasingly important in offering effective treatment for patients in clinical practice. This review focuses on the role of autophagy in 5-FU-induced tumor suppression and cancer therapy in the digestive system.Data Sources:All articles published in English from 1996 to date those assess the synergistic effect of autophagy and 5-FU in gastrointestinal cancer therapy were identified through a systematic online search by use of PubMed. The search terms were “autophagy” and “5-FU” and (“colorectal cancer” or “hepatocellular carcinoma” or “pancreatic adenocarcinoma” or “esophageal cancer” or “gallbladder carcinoma” or “gastric cancer”).Study Selection:Critical reviews on relevant aspects and original articles reporting in vitro and/or in vivo results regarding the efficiency of autophagy and 5-FU in gastrointestinal cancer therapy were reviewed, analyzed, and summarized. The exclusion criteria for the articles were as follows: (1) new materials (e.g., nanomaterial)-induced autophagy; (2) clinical and experimental studies on diagnostic and/or prognostic biomarkers in digestive system cancers; and (3) immunogenic cell death for anticancer chemotherapy.Results:Most cell and animal experiments showed inhibition of autophagy by either pharmacological approaches or via genetic silencing of autophagy regulatory gene, resulting in a promotion of 5-FU-induced cancer cells death. Meanwhile, autophagy also plays a pro-death role and may mediate cell death in certain cancer cells where apoptosis is defective or difficult to induce. The dual role of autophagy complicates the use of autophagy inhibitor or inducer in cancer chemotherapy and generates inconsistency to an extent in clinic trials.Conclusion:Autophagy might be a therapeutic target that sensitizes the 5-FU treatment in gastrointestinal cancer.

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Ammonium chloride inhibits autophagy of hepatocellular carcinoma cells through SMAD2 signaling

Cited by 18 publications

References 17 publications

Ammonia produces pathological changes in human hepatic stellate cells and is a target for therapy of portal hypertension

Ammonia produces pathological changes in human hepatic stellate cells and is a target for therapy of portal hypertension

The metabolic waste ammonium regulates mTORC2 and mTORC1 signaling

Autophagy in 5-Fluorouracil Therapy in Gastrointestinal Cancer

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