JTC801 Induces pH-dependent Death Specifically in Cancer Cells and Slows Growth of Tumors in Mice

Song, Xinxin; Zhu, Shan; Xie, Yangchun; Liu, Jiao; Sun, Lingyi; Zeng, Dexing; Wang, Pengcheng; Ma, Xiaochao; Kroemer, Guido; Bartlett, David L.; Billiar, Timothy R.; Lotze, Michael T.; Zeh, Herbert J.; Kang, Rui; Tang, Daolin

doi:10.1053/j.gastro.2017.12.004

Cited by 133 publications

(129 citation statements)

References 18 publications

(17 reference statements)

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“…cDNA from various cell samples was amplified using real-time quantitative PCR with specific primers (Table S2). The data were normalized to 18S RNA and the fold change was calculated via the 2 −ΔΔCt method (Song et al, 2018; Zhu et al, 2017). Relative concentrations of mRNA were expressed in arbitrary units based on the untreated group, which was assigned a value of 1.…”

Section: Star Methodsmentioning

confidence: 99%

Lipid Peroxidation Drives Gasdermin D-Mediated Pyroptosis in Lethal Polymicrobial Sepsis

Kang

Zeng

Zhu

et al. 2018

Cell Host & Microbe

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431

301

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Sepsis is a life-threatening condition caused by pathogen infection and associated with pyroptosis. Pyroptosis occurs upon activation of proinflammatory caspases and their subsequent cleavage of gasdermin D (GSDMD), resulting in GSDMD N-terminal fragments that form membrane pores to induce cell lysis. Here, we show that antioxidant defense enzyme glutathione peroxidase 4 (GPX4) and its ability to decrease lipid peroxidation, negatively regulate macrophage pyroptosis, and septic lethality in mice. Conditional Gpx4 knockout in myeloid lineage cells increases lipid peroxidation-dependent caspase-11 activation and GSDMD cleavage. The resultant N-terminal GSDMD fragments then trigger macrophage pyroptotic cell death in a phospholipase C gamma 1 (PLCG1)-dependent fashion. Administration of the antioxidant vitamin E that reduces lipid peroxidation, chemical inhibition of PLCG1, or genetic Caspase-11 deletion or Gsdmd inactivation prevents polymicrobial sepsis in Gpx4 mice. Collectively, this study suggests that lipid peroxidation drives GSDMD-mediated pyroptosis and hence constitutes a potential therapeutic target for lethal infection.

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Section: Star Methodsmentioning

confidence: 99%

Lipid Peroxidation Drives Gasdermin D-Mediated Pyroptosis in Lethal Polymicrobial Sepsis

Kang

Zeng

Zhu

et al. 2018

Cell Host & Microbe

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431

301

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“…Furthermore, JTC-801 demonstrated its anticancer effect in the ovarian cancer SKOV3 cell line, particularly on cell growth and metastasis (16). Song et al (12) reported that JTC-801 may be used for the treatment of pancreatic cancer. Similarly, the present study revealed the inhibitory effect of the drug on Hep G2 hepatoblastoma cells.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, ORL1 may antagonize lipopolysaccharide-stimulated proliferation, migration and inflammatory signalling in human glioblastoma U87 cells (11). In a screening of agents that interact with GPCR pathways, Song et al (12) revealed that JTC-801 induces pH-dependent cell death (alkaliptosis) specifically in cancer cells, including pancreatic ductal adenocarcinoma cells, by reducing the expression of carbohydrate antigen 9, which is increased in human cancer tissues. JTC-801 may be used in the development of treatment for pancreatic cancer.…”

Section: Introductionmentioning

confidence: 99%

JTC‑801 inhibits the proliferation and metastasis of the Hep G2 hepatoblastoma cell line by regulating the phosphatidylinositol 3‑kinase/protein kinase B signalling pathway

Zhao

2018

Oncol Lett

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The increased worldwide mortality rate due to liver cancer may be attributed to the aggressive nature of the disease. Signal transduction through G-protein-coupled receptors (GPCRs) can affect a number of aspects of cancer biology, including invasion, migration and vascular remodelling. JTC-801, a novel GPCR antagonist, has demonstrated promising anticancer effects in adenocarcinoma and osteosarcoma cells. In the present study, the effect of JTC-801 on the proliferation and migration of hepatoblastoma Hep G2 cells was investigated. The Cell Counting Kit-8 assay revealed that JTC-801 markedly suppressed the growth of the Hep G2 cells. Additionally, JTC-801 significantly inhibited cell invasion and migration in a Transwell assay. Furthermore, the expression of anti-apoptotic protein B-cell lymphoma 2 decreased and the expression of the pro-apoptotic proteins active caspase-3 and apoptosis regulator BAX increased in the Hep G2 cells following JTC-801 treatment. Additionally, JTC-801 suppressed the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signalling pathway in the Hep G2 cells. Therefore, the present study revealed that JTC-801 can induce the apoptosis of Hep G2 cells by regulating the PI3K/AKT signalling pathway, which suggests that JTC-801 may be a potential novel drug target for clinical liver cancer treatment. phosphatidylinositol 3-kinase; AKT, protein kinase B; mTOR, mechanistic target of rapamycin; Bcl-2, B-cell lymphoma 2; Bax, apoptosis regulator BAX; P70S6K, P70S6 kinase; CCK-8, Cell Counting Kit-8; FITC, fluorescein isothiocyanate; PI, propidium iodide

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“…Alkaliptosis is a unique pHdependent form of RCD driven by intracellular alkalinization [27]. Song et al showed that JTC801 can induce a pHdependent cell death in human pancreatic cancer cells by activating NF-κB [28]. is form was found to be distinct from ferroptosis, necroptosis, and autophagy, and was defined as alkaliptosis.…”

Section: Nrf2/ho-1 Signaling Axis In Alkaliptosismentioning

confidence: 99%

“…Although NF-κB inhibitors can inhibit alkaliptosis [29], no effect of Nrf2 knockout alters JTC801-induced cell death [28]. However, as pathological significance of alkaloptosis and its core effector molecules are still being studied, the specific relationship is not yet clear.…”

Section: Nrf2/ho-1 Signaling Axis In Alkaliptosismentioning

confidence: 99%

The Nrf-2/HO-1 Signaling Axis: A Ray of Hope in Cardiovascular Diseases

Zhang

Lei

et al. 2020

Cardiology Research and Practice

109

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Cardiovascular disease, which can lead to angina and shortness of breath, remains one of the most serious threats to human health. Owing to its imperceptible symptoms, it is difficult to determine the pathogenesis and treatment methods for cardiovascular disease. Nuclear factor erythropoietin-2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) is a protein found in all cells of the human body. It is activated, transferred to the nucleus, and bound to DNA by antioxidant response elements (AREs). As a regulator of the antioxidant system, it upregulates the expression of HO-1 to reduce oxidative stress. Nrf2/HO-1 also has the ability to modulate calcium levels to prevent ferroptosis, pyroptosis, autophagy, programmed cell necrosis, alkaliptosis, and clockophagy. In view of the importance of Nrf2/HO-1 in the regulation of homeostasis, this review summarizes current research on the relationship between cardiovascular disease and Nrf2/HO-1. Normal cardiovascular diseases, such as viral myocarditis and myocardial ischemia-reperfusion injury, have been treated with Nrf2/HO-1. Rheumatic heart disease, cardiac tumors, arteriosclerosis, arrhythmia, hypertensive heart disease, and myocardial infarction have also been treated during experiments. Research has demonstrated the clinical application of Nrf2/HO-1 in pediatric cardiovascular disease; further clinical trials will help elucidate the potential of the Nrf2/HO-1 signaling axis.

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JTC801 Induces pH-dependent Death Specifically in Cancer Cells and Slows Growth of Tumors in Mice

Cited by 133 publications

References 18 publications

Lipid Peroxidation Drives Gasdermin D-Mediated Pyroptosis in Lethal Polymicrobial Sepsis

Lipid Peroxidation Drives Gasdermin D-Mediated Pyroptosis in Lethal Polymicrobial Sepsis

JTC‑801 inhibits the proliferation and metastasis of the Hep G2 hepatoblastoma cell line by regulating the phosphatidylinositol 3‑kinase/protein kinase B signalling pathway

The Nrf-2/HO-1 Signaling Axis: A Ray of Hope in Cardiovascular Diseases

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