Liver acid sphingomyelinase inhibits growth of metastatic colon cancer

Osawa, Yosuke; Suetsugu, Atsushi; Matsushima‐Nishiwaki, Rie; Yasuda, Ichiro; Saibara, Toshiji; Moriwaki, Hisataka; Seishima, Mitsuru; Kozawa, Osamu

doi:10.1172/jci65188

Cited by 32 publications

(28 citation statements)

References 52 publications

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“…The upregulated cytokines [29, 30] we detected in culture supernatants of macrophages are known to promote tumor progression. Therefore, we further hypothesize that HG-NVs might enhance or increase tumor progression.…”

Section: Resultsmentioning

confidence: 99%

Isolation, identification, and characterization of novel nanovesicles

et al. 2016

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Extracellular microvesicles (EVs) have been recognized for many potential clinical applications including biomarkers for disease diagnosis. In this study, we identified a major population of EVs by simply screening fluid samples with a nanosizer. Unlike other EVs, this extracellular nanovesicle (named HG-NV, HG-NV stands for HomoGenous nanovesicle as well as for Huang-Ge- nanovesicle) can be detected with a nanosizer with minimal in vitro manipulation and are much more homogenous in size (8–12 nm) than other EVs. A simple filtration platform is capable of separating HG-NVs from peripheral blood or cell culture supernatants. In comparison with corresponding exosome profiles, HG-NVs released from both mouse and human breast tumor cells are enriched with RNAs. Tumor derived HG-NVs are more potent in promoting tumor progression than exosomes. In summary, we identified a major subset of EVs as a previously unrecognized nanovesicle. Tumor cell derived HG-NVs promote tumor progression. Molecules predominantly present in breast tumor HG-NVs have been identified and characterized. This discovery may have implications in advancing both microvesicle biology research and clinical management including potential used as a biomarker.

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Section: Resultsmentioning

confidence: 99%

Isolation, identification, and characterization of novel nanovesicles

et al. 2016

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“…Another somewhat contradictory report showed that treatment of implanted hepatocellular carcinoma cells with both sorafenib (a multi-serine/threonine kinase inhibitor) and recombinant ASMase increased cell death relative to sorafenib alone [18]. This is backed up by a study showing that liver ASMase activity can inhibit the growth of metastatic colon cancer [19]. It therefore appears that the activity of ASMase in promoting cancer death may be tied to both the cell type and the protein kinases that are present.…”

Section: Part 1 Sphingolipids and The Initiation Of Apoptosismentioning

confidence: 99%

Evolving concepts in cancer therapy through targeting sphingolipid metabolism

Truman

Garcı́a-Barros

Obeid

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

111

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Traditional methods of cancer treatment are limited in their efficacy due to both inherent and acquired factors. Many different studies have shown that the generation of ceramide in response to cytotoxic therapy is generally an important step leading to cell death. Cancer cells employ different methods to both limit ceramide generation and to remove ceramide in order to become resistant to treatment. Furthermore, sphingosine kinase activity, which phosphorylates sphingosine the product of ceramide hydrolysis, has been linked to multidrug resistance, and can act as a strong survival factor. This review will examine several of the most frequently used cancer therapies and their effect on both ceramide generation and the mechanisms employed to remove it. The development and use of inhibitors of sphingosine kinase will be focused upon as an example of how targeting sphingolipid metabolism may provide an effective means to improve treatment response rates and reduce associated treatment toxicity.

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“…Notably in mice, an inhibitor of the interaction between β‐catenin and cyclic adenosine monophosphate‐response element‐binding protein‐binding protein (CBP) reduces liver fibrosis mediated by bile‐duct ligation (BDL), CCl 4 , or hepatitis C virus and prevents HSC activation, which results in a reduction of collagen expression in vitro . Liver macrophages contribute to liver fibrosis; depletion of liver macrophages suppresses liver fibrosis following BDL and decreases myofibroblasts in a liver tumor . Moreover, inhibition of CBP/β‐catenin promotes liver fibrosis resolution by macrophages .…”

Section: Introductionmentioning

confidence: 99%

Tumor necrosis factor‐α‐mediated hepatocyte apoptosis stimulates fibrosis in the steatotic liver in mice

Osawa

Kojika

Hayashi

et al. 2018

Hepatology Communications

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Hepatocyte apoptosis has been implicated in the progression of nonalcoholic steatohepatitis. However, it is unclear whether the induction of tumor necrosis factor (TNF)‐α‐mediated hepatocyte apoptosis in the simple fatty liver triggers liver fibrosis. To address this question, high‐fat diet‐fed mice were repeatedly administered D‐galactosamine, which increases the sensitivity of hepatocytes to TNF‐α‐mediated apoptosis. In mice treated with a high‐fat diet plus D‐galactosamine, hepatocyte apoptosis and liver fibrosis were induced, whereas both apoptosis and fibrosis were inhibited in these mice following gut sterilization with antimicrobials or knockout of TNF‐α. Furthermore, liver fibrosis was diminished when hepatocyte apoptosis was inhibited by expressing a constitutively active inhibitor of nuclear factor κB kinase subunit β. Thus, hepatocyte apoptosis induced by intestinal dysbiosis or TNF‐α up‐regulation in the steatotic liver caused fibrosis. Organ fibrosis, including liver fibrosis, involves the interaction of cyclic adenosine monophosphate‐response element‐binding protein‐binding protein (CBP) and β‐catenin. Here, hepatocyte‐specific CBP‐knockout mice showed reduced liver fibrosis accompanied by hepatocyte apoptosis diminution; notably, liver fibrosis was also decreased in mice in which CBP was specifically knocked out in collagen‐producing cells because the activation of these cells was now suppressed. Conclusion: TNF‐α‐mediated hepatocyte apoptosis induced fibrosis in the steatotic liver, and inhibition of CBP/β‐catenin signaling attenuated the liver fibrosis due to the reduction of hepatocyte apoptosis and suppression of the activation of collagen‐producing cells. Thus, targeting CBP/β‐catenin may represent a new therapeutic strategy for treating fibrosis in nonalcoholic steatohepatitis. (Hepatology Communications 2018;2:407‐420)

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Liver acid sphingomyelinase inhibits growth of metastatic colon cancer

Cited by 32 publications

References 52 publications

Isolation, identification, and characterization of novel nanovesicles

Isolation, identification, and characterization of novel nanovesicles

Evolving concepts in cancer therapy through targeting sphingolipid metabolism

Tumor necrosis factor‐α‐mediated hepatocyte apoptosis stimulates fibrosis in the steatotic liver in mice

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