Characteristics of the growth inhibition and cytotoxicity of long-chain (sphingoid) bases for Chinese hamster ovary cells

Stevens, Victoria L.; Nimkar, Sanjay; Jamison, W.C.L.; Liotta, Dennis; Merrill, Alfred H.

doi:10.1016/0167-4889(90)90171-9

Cited by 86 publications

(28 citation statements)

References 47 publications

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“…The cytotoxicity of 1-deoxySa is similar to that previously seen for sphingoid bases (39), although the findings with DU-145 cells indicate that removal of the 1-hydroxylgroup has enhanced the potency somewhat. It is possible that some of the biological effects of 1-deoxySa occur after its metabolism to 1-deoxyDHCer, or due to interference with the metabolism of another sphingolipid, such as by inhibition of sphingosine kinase.…”

Section: Discussionsupporting

confidence: 59%

Ceramide Synthase Inhibition by Fumonisin B1 Causes Accumulation of 1-Deoxysphinganine

Zitomer

Mitchell

Voss

et al. 2009

Journal of Biological Chemistry

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216

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13 C]deoxySa. 1-DeoxySa was elevated in FB 1 -treated cells and mouse liver and kidney, and its cytotoxicity was greater than or equal to that of Sa for LLC-PK 1 and DU-145 cells. Therefore, this compound is likely to contribute to pathologies associated with fumonisins. In the absence of FB 1 , substantial amounts of 1-deoxySa are made and acylated to N-acyl-1-deoxySa (i.e. 1-deoxydihydroceramides). Thus, these compounds are an underappreciated category of bioactive sphingoid bases and "ceramides" that might play important roles in cell regulation. Fumonisins (FB)2 cause diseases of horses, swine, and other farm animals and are regarded to be potential risk factors for human esophageal cancer (1) and, more recently, birth defects (2). Studies of this family of mycotoxins, and particularly of the highly prevalent subspecies fumonisin B 1 (FB 1 ) (reviewed in Refs. 1 and 2), have established that FB 1, is both toxic and carcinogenic for laboratory animals, with the liver and kidney being the most sensitive target organs (3, 4). Other FB are also toxic, but their carcinogenicity is unknown.FB are potent inhibitors of ceramide synthase(s) (CerS) (5), the enzymes responsible for acylation of sphingoid bases using fatty acyl-CoA for sphingolipid biosynthesis de novo and recycling pathways (6). As a consequence of this inhibition, the substrates sphinganine (Sa) and, usually to a lesser extent, sphingosine (So), accumulate and are often diverted to sphinganine 1-phosphate (Sa1P) and sphingosine 1-phosphate (S1P), respectively (7), while the product N-acylsphinganines (dihydroceramides), N-acylsphingosines (ceramides, Cer), and more complex sphingolipids decrease (5, 7). This disruption of sphingolipid metabolism has been proposed to be responsible for the toxicity, and possibly carcinogenicity, of FB, based on mechanistic studies with cells in culture (5,(7)(8)(9). This has been borne out by a number of animal feeding studies that have correlated the elevation of Sa in blood, urine, liver, and kidney with liver and kidney toxicity (4, 7, 10, 11).Most of the mechanistic studies have focused on the accumulation of free Sa and other sphingoid bases, because these compounds are highly cytotoxic, although the large number of bioactive metabolites in this pathway make it likely that multi-

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Section: Discussionsupporting

confidence: 59%

Ceramide Synthase Inhibition by Fumonisin B1 Causes Accumulation of 1-Deoxysphinganine

Zitomer

Mitchell

Voss

et al. 2009

Journal of Biological Chemistry

Self Cite

216

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“…Our data indicate that caspase-3-like proteases are key regulators in the apoptotic process induced by sphingosine. Although several sphingolipids (such as sphingosine, sphingosine 1-phosphate and N,N-dimethylsphingosine) have been demonstrated to elicit apoptotic effects in a number of cancer cell lines [11,31], the involvement of caspase-3-like proteases in spingosine-activated apoptosis is a new finding. In the study of the induction of the catalytic activity of caspase-3 by sphingosine, cells treated with etoposide were always included to verify the experimental results.…”

Section: Discussionmentioning

confidence: 99%

Activation of caspase-3-like proteases in apoptosis induced by sphingosine and other long-chain bases in Hep3B hepatoma cells

Hung

Chang

Chuang

1999

Biochemical Journal

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Sphingosine and other long-chain bases (including sphinganine, dimethylsphingosine and stearylamine), but not octylamine (a short-chain analogue of sphinganine), induced apoptosis in Hep3B hepatoma cells. Because both -and -erythrosphingosine and stearylamine exert potent apoptotic effects on Hep3B cells, it is possible that these long-chain bases may activate apoptosis by inhibiting protein kinase C (PKC) activity. However, pretreatment with the PKC activator PMA could not rescue cells from apoptosis triggered by long-chain bases. Therefore the involvement of PKC in this apoptotic process requires further characterization. We also investigated whether these long-chain bases might be metabolized into ceramide in order to elicit their apoptotic action. We found that long-chain bases acted independently of ceramide in the induction of apoptosis, since addition of fumonisin B1, a fungal agent which effectively inhibits ceramide synthesis from sphingosine, did not protect against apoptosis. Additionally, we found that sphingosine-

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“…[60][61][62] Like ceramide, sphingosine exerts divergent effects depending on cell type. 9 Sphingosine promotes apoptosis in U937 cells 27,63,64 and prostate cancer cells, 65 induces cell arrest in Chinese hamster ovary cells, 66 and promotes proliferation of Swiss 3T3 cells. 67 Sphingosine has different effects on stress signaling pathways when compared to ceramide.…”

Section: Other Molecules Involved In Ceramide Biosynthesis Regulate Cmentioning

confidence: 99%

Ceramide regulates cellular homeostasis via diverse stress signaling pathways

2001

Leukemia

173

111

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The sphingolipid ceramide is an important second signal molecule that regulates diverse signaling pathways involving apoptosis, cell senescence, the cell cycle, and differentiation. For the most part, ceramide's effects are antagonistic to growth and survival. Interestingly, ceramide and the pro-growth agonist, diacylglycerol (DAG) appear to be regulated simultaneously but in opposite directions in the sphingomyelin cycle. While ceramide stimulates signal transduction pathways that are associated with cell death or at least are inhibitory to cell growth (eg stress-activated protein kinase, SAPK, pathways), DAG activates the classical and novel isoforms of the protein kinase C (PKC) family. These PKC isoforms are associated with cell growth and cell survival.

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Characteristics of the growth inhibition and cytotoxicity of long-chain (sphingoid) bases for Chinese hamster ovary cells

Cited by 86 publications

References 47 publications

Ceramide Synthase Inhibition by Fumonisin B1 Causes Accumulation of 1-Deoxysphinganine

Ceramide Synthase Inhibition by Fumonisin B1 Causes Accumulation of 1-Deoxysphinganine

Activation of caspase-3-like proteases in apoptosis induced by sphingosine and other long-chain bases in Hep3B hepatoma cells

Ceramide regulates cellular homeostasis via diverse stress signaling pathways

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