Dietary sphingolipids suppress a subset of preneoplastic rat liver lesions exhibiting high PTEN, low phospho-Akt and high levels of ceramide species

Silins, Ilona; Högberg, Johan; Stenius, Ulla

doi:10.1016/j.fct.2006.04.001

Cited by 6 publications

(5 citation statements)

References 57 publications

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“…The lack of apoptosis was verified by evaluating the shape of the nuclei in H&E stained sections-condensed or fragmented nuclei of epithelial cells were rarely detected, indicating that orally administered SM did not induce apoptosis in the xenografts. This low rate of apoptosis in MCF10AT1 xenografts is not specific for our study but has been reported before in MCF10AT1 cells grown in three-dimensional cultures 36 or as xenografts 37,38 These results confirm our previous observations and the reports of other groups that dietary sphingolipids do not induce apoptosis above normal levels in the colon, 16,17 liver 35,39,40 or spleen. 40 Instead, we have previously observed a suppression of aberrant proliferation in the colonic mucosa.…”

Section: Sphingomyelin Reduced Cell Proliferation But Did Not Induce ...supporting

confidence: 92%

“…27 These results indicate that SM supplements suppressed or delayed the progression of these lesions, confirming our hypothesis that diet-derived SM metabolites are sufficient to exhibit a systemic effect and suppress breast cancer progression without causing side effects. Thus, dietary sphingolipids are not only effective against colon (our previous studies) and liver cancer 35 but can successfully target cancer of distant sites in the body. Whether dietary sphingolipids are as effective against more aggressive breast cancer lesions is currently being investigated in our laboratory.…”

Section: Resultsmentioning

confidence: 85%

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Suppression of breast xenograft growth and progression in nude mice: implications for the use of orally administered sphingolipids as chemopreventive agents against breast cancer

et al. 2010

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Sphingolipids are lipid messengers involved in the regulation of many different cellular processes. Sphingolipid enzymes and bioactive metabolites have been targets of in vitro and in vivo efforts to suppress cancer growth, progression and metastasis of various cancer types. Dietary sphingomyelin effectively suppressed colon cancer in several rodent models without causing toxic side effects. In the present study, we determined if the effect of sphingolipid metabolites derived from the hydrolysis of dietary sphingomyelin is restricted to the intestinal tract or if their systemic concentrations are sufficient to suppress cancers of distant sites. For these studies, we used MCF10AT1 cells, a model for progressive breast cancer, injected into the mammary fatpad of nude mice as a single cell suspension. The mice were fed 0.1% sphingomyelin supplements in a semi-purified AIN76A control diet when the lesions were palpable. The study was terminated when the first lesions had grown to 5 mm. In the sphingomyelin-fed group, there was a trend to smaller lesion size and, importantly, a delayed progression to more malignant stages without apparent side effects. This may be the result of significantly reduced rates of proliferation and angiogenesis, while no increase of apoptosis was detected. Changes in aberrantly expressed proteins in the sphingomyelin-fed group, such as E-cadherin, VEGF and sphingosine kinase-1, may be associated with the suppression of tumor growth. These results demonstrate that diet-derived sphingolipids can efficiently suppress the growth and progression of MCF10AT1 xenografts, suggesting that dietary sphingomyelin may also be effective against cancers of other sites.

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Section: Sphingomyelin Reduced Cell Proliferation But Did Not Induce ...supporting

confidence: 92%

Section: Resultsmentioning

confidence: 85%

Suppression of breast xenograft growth and progression in nude mice: implications for the use of orally administered sphingolipids as chemopreventive agents against breast cancer

et al. 2010

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“…An involvement of P2X4 in phosphatase cross-talk suggest a coupling to cell death and repair processes (46), and we analyzed regenerative preneoplastic liver lesions in rats, induced after repeated toxic doses of the potent genotoxic carcinogen diethylnitrosamine (47). The mechanistic scenario for these chemically induced lesions includes several rounds of cellular damage-repair cycles and a dependence on TGFβ signaling (48).…”

Section: Resultsmentioning

confidence: 99%

Phosphatase and Tensin Homolog Deleted on Chromosome 10 (PTEN) and PH Domain and Leucine-rich Repeat Phosphatase Cross-talk (PHLPP) in Cancer Cells and in Transforming Growth Factor β-Activated Stem Cells

Ghalali

Högberg

et al. 2014

Journal of Biological Chemistry

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Background: The oncogene Akt is regulated by phosphatases.Results: Akt phosphatases cross-talk in prostate cancer cells and in transforming growth factor β1-activated stem cells but not in non-transformed cells.Conclusion: This back-up mechanism facilitates invasive migration of prostate stem and cancer cells.Significance: Characterization of Akt regulation may lead to a better understanding of tumor development and to novel strategies for treatment.

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“…In rat hepatocarcinogenesis, there is a subpopulation of GST‐P‐positive liver cell foci exhibiting increased expression of PTEN and decreased expression of the phosphorylated (activated) form of Akt (phospho‐Akt), as well as high levels of ceramide species that are sensitive to sphingomyelin as a chemopreventive target. ( 12 ) On the other hand, in a two‐stage hepatocarcinogenesis model, we recently obtained a contradictory result showing a lack of PTEN expression in a majority of GST‐P‐positive foci induced by promotion with phenob‐arbito (PB) or fenben‐dazole (FB), in contrast to the constitutive expression of PTEN in surrounding hepatocytes. ( 13 ) This result suggests a decrease in the tumor suppressor function of PTEN by down‐regulation even during the early stage of hepatocarcinogenesis.…”

mentioning

confidence: 99%

Crosstalk between PTEN/Akt2 and TGFβ signaling involving EGF receptor down‐regulation during the tumor promotion process from the early stage in a rat two‐stage hepatocarcinogenesis model

et al. 2009

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The present study investigated the involvement of signaling of phosphatase and tensin homolog deleted on chromosome 10 (PTEN)/ protein kinase B (Akt) and transforming growth factor-b (TGFb) as well as receptor tyrosine kinases in the tumor promotion processes in a two-stage hepatocarcinogenesis model using male F344 rats. The cellular localization of related molecules was examined in liver cell foci expressing glutathione S-transferase placental form (GST-P) at the early stage of tumor promotion by fenbendazole (FB), piperonyl butoxide, or thioacetamide. Distribution in the liver cell foci and neoplastic lesions positive for GST-P was also examined at the later stage of FB promotion. In contrast to the initiation-alone cases, subpopulations of GST-P-positive foci induced by promotion for 6 weeks, regardless of the promoting chemicals used, enhanced down-regulation of PTEN and up-regulation of phosphorylated (active) Akt2 and phosphorylated substrate(s) of Akt-kinase activity. Also, up-regulation of TGFb receptor I and down-regulation of epidermal growth factor receptor (EGFR) were enhanced in the subpopulation of GST-P-positive foci in all promoted cases. A similar pattern of cellular distribution of these molecules was also observed in the neoplastic lesions at the late stage. These results suggest a crosstalk between Akt2 and TGFb signaling that involves a mechanism requiring EGFR downregulation during the entire tumor promotion process starting from the early stage. In particular, a shift in subcellular localization of phosphorylated substrate(s) of Akt from the cell membrane in liver cell foci to the cytoplasm in carcinomas was observed, suggesting an alteration of the function or activity of the corresponding molecule(s). (Cancer Sci 2009; 100: 813-820) I n a rat two-stage hepatocarcinogenesis model, altered liver cell foci immunoreactive for glutathiuone S-transferase placental form (GST-P) have been shown to increase in number and area because of tumor promotion with hepatocarcinogens, in accordance with the hepatocarcinogenic potential; therefore, these foci have been confirmed as preneoplastic lesions of liver cells.(1,2) However, only a few studies have examined the roles of cellular signaling and molecular linkage in the growth and development of the liver cell foci. (3)(4)(5)(6) Akt is a serine/threonine kinase that is a central regulator of widely divergent cellular processes, including proliferation, differentiation, migration, survival, and metabolism.(7) Akt is activated by a variety of stimuli, through growth factor receptors, in a phosphatidylinositol 3-kinase (PI3K)-dependent manner, and it is also negatively regulated by the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN).(8) A disruption of normal Akt/PTEN signaling frequently occurs in many human cancers, and thus these molecules play an important role in cancer development, progression, and therapeutic resistance.(9,10) To date, three members of the Akt family have been identified in mammals: Akt1, Akt2, and...

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Dietary sphingolipids suppress a subset of preneoplastic rat liver lesions exhibiting high PTEN, low phospho-Akt and high levels of ceramide species

Cited by 6 publications

References 57 publications

Suppression of breast xenograft growth and progression in nude mice: implications for the use of orally administered sphingolipids as chemopreventive agents against breast cancer

Suppression of breast xenograft growth and progression in nude mice: implications for the use of orally administered sphingolipids as chemopreventive agents against breast cancer

Phosphatase and Tensin Homolog Deleted on Chromosome 10 (PTEN) and PH Domain and Leucine-rich Repeat Phosphatase Cross-talk (PHLPP) in Cancer Cells and in Transforming Growth Factor β-Activated Stem Cells

Crosstalk between PTEN/Akt2 and TGFβ signaling involving EGF receptor down‐regulation during the tumor promotion process from the early stage in a rat two‐stage hepatocarcinogenesis model

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