Pharmacological inhibition or small interfering RNA targeting acid ceramidase sensitizes hepatoma cells to chemotherapy and reduces tumor growth in vivo

Morales, Albert; Parı́s, Raquel; Villanueva, Alberto; Llacuna, Laura; Garcı́a-Ruiz, Carmen; Fernández-Checa, José C.

doi:10.1038/sj.onc.1209834

Cited by 95 publications

(85 citation statements)

References 45 publications

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“…5A). The increase in long-chain ceramides in cells treated with C2-ceramide was of similar magnitude to that observed in cells treated with the chemotherapeutic daunorubicin (DNR), a drug known to increase ceramide levels (5,23,24), and in response to growth factor withdrawal, also previously shown to increase ceramide levels (2). With all stimuli, the largest increase was in C16:0 ceramide.…”

Section: Resultssupporting

confidence: 51%

“…Ceramide plays a particularly well-established role in cancer. Decreasing cellular ceramide levels increases tumor growth and metastasis and can lead to multidrug resistance, a major cause of cancer treatment failure (2,5,6). The ability of ceramide to trigger programmed cell death in response to growth factor withdrawal, death receptor ligation, hypoxia, and chemotherapeutic drugs is likely integral to its role in suppressing cancer initiation and progression.…”

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confidence: 99%

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Ceramide starves cells to death by downregulating nutrient transporter proteins

Guenther

Peralta

Rosales

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

170

212

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Ceramide induces cell death in response to many stimuli. Its mechanism of action, however, is not completely understood. Ceramide induces autophagy in mammalian cells maintained in rich media and nutrient permease downregulation in yeast. These observations suggested to us that ceramide might kill mammalian cells by limiting cellular access to extracellular nutrients. Consistent with this proposal, physiologically relevant concentrations of ceramide produced a profound and specific downregulation of nutrient transporter proteins in mammalian cells. Blocking ceramide-induced nutrient transporter loss or supplementation with the cell-permeable nutrient, methyl pyruvate, reversed ceramide-dependent toxicity. Conversely, cells became more sensitive to ceramide when nutrient stress was increased by acutely limiting extracellular nutrients, inhibiting autophagy, or deleting AMP-activated protein kinase (AMPK). Observations that ceramide can trigger either apoptosis or caspase-independent cell death may be explained by this model. We found that methyl pyruvate (MP) also protected cells from ceramide-induced, nonapoptotic death consistent with the idea that severe bioenergetic stress was responsible. Taken together, these studies suggest that the cellular metabolic state is an important arbiter of the cellular response to ceramide. In fact, increasing nutrient demand by incubating cells in high levels of growth factor sensitized cells to ceramide. On the other hand, gradually adapting cells to tolerate low levels of extracellular nutrients completely blocked ceramide-induced death. In sum, these results support a model where ceramide kills cells by inducing intracellular nutrient limitation subsequent to nutrient transporter downregulation.autophagy ͉ caspase-independent cell death ͉ daunorubicin ͉ bioenergetics ͉ sphingolipid C eramide and related sphingolipids play an evolutionarily conserved role in the cellular response to stress by regulating cell growth, differentiation, senescence, and survival (1). Uncovering the mechanisms by which ceramide regulates these processes is of paramount importance given the wide range of human diseases that result from altered ceramide metabolism including cancer, type II diabetes, and neurodegenerative disease (2-4). Ceramide plays a particularly well-established role in cancer. Decreasing cellular ceramide levels increases tumor growth and metastasis and can lead to multidrug resistance, a major cause of cancer treatment failure (2, 5, 6). The ability of ceramide to trigger programmed cell death in response to growth factor withdrawal, death receptor ligation, hypoxia, and chemotherapeutic drugs is likely integral to its role in suppressing cancer initiation and progression. Although many of the downstream, executioner pathways that are activated by ceramide are known, how ceramide triggers these pathways is not completely understood.Autophagy, a process by which cells catabolize their own components, is induced in ceramide-treated cells (7-9). Autophagy has been conserved through...

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Section: Resultssupporting

confidence: 51%

mentioning

confidence: 99%

Ceramide starves cells to death by downregulating nutrient transporter proteins

Guenther

Peralta

Rosales

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

170

212

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“…ASAH1 down-regulation sensitized cells to the treatment, probably through increased levels of ceramide. Sensitization of cells by ASAH1 down-regulation (20) or by enzymatic inhibition (19) has already been reported in other cancer models. Interestingly, down-regulation of other ceramidases such as neutral (ASAH2) or alkaline ceramidase 2 (ASAH3L) did not recapitulate the sensitizing effects of ASAH1 silencing (only ASAH3L silencing slightly increased the sensitivity of cells to DTIC; see supplemental Fig.…”

Section: Discussionmentioning

confidence: 98%

“…Also, pharmacological inhibition of aCDase has been reported to completely prevent tumor growth of human colon cancer cells metastatic to the liver (18) and of prostate cancer xenografts (19). In addition, down-regulation of ASAH1 using specific siRNA reduced tumor growth in an in vivo model of hepatocellular carcinoma (20).…”

mentioning

confidence: 99%

Acid Ceramidase Expression Modulates the Sensitivity of A375 Melanoma Cells to Dacarbazine

Bedia

Casas²,

Andrieu‐Abadie

et al. 2011

Journal of Biological Chemistry

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Dacarbazine (DTIC) is the treatment of choice for metastatic melanoma, but its response in patients remains very poor. Ceramide has been shown to be a death effector and to play an important role in regulating cancer cell growth upon chemotherapy. Among ceramidases, the enzymes that catabolize ceramide, acid ceramidase (aCDase) has been implicated in cancer progression. Here we show that DTIC elicits a time-and dosedependent decrease of aCDase activity and an increase of intracellular ceramide levels in human A375 melanoma cells. The loss of enzyme activity occurred as a consequence of reactive oxygen species-dependent activation of cathepsin B-mediated degradation of aCDase. These events preceded autophagic features and loss of cell viability. Down-regulation of acid but not neutral or alkaline ceramidase 2 resulted in elevated levels of ceramide and sensitization to the toxic effects of DTIC. Conversely, inducible overexpression of acid but not neutral ceramidase reduced ceramide levels and conferred resistance to DTIC. In conclusion, we report that increased levels of ceramide, due to enhanced degradation of aCDase, are in part responsible for the cell death effects of DTIC. These results suggest that downregulation of aCDase alone or in combination with DTIC may represent a useful tool in the treatment of metastatic melanoma.

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“…6 Changes in sphingolipid metabolism that reduce ceramide levels not only promote tumorigenesis, but multidrug resistance follows from mutations that block the ceramide production normally triggered by chemotherapy. [7][8][9][10] Autophagy is altered in these same conditions characterized by disrupted ceramide metabolism. Protective autophagy increases in the pancreatic islets of animals maintained on a diabetogenic, high-fat diet, and plays an important but complex role in tumor initiation and progression.…”

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confidence: 99%