Ceramide starves cells to death by downregulating nutrient transporter proteins (PNAS, 2008, 105:17402-17407)

報告日期: 2009/04/07
報告時間: 15:10/16:00
報告學生: 黃薇靜(英文報告)
講評老師: 楊倍昌
附件下載:

http://basicmed.med.ncku.edu.tw/admin/up_img/980407-1.pdf

Ceramide starves cells to death by downregulating nutrient transporter proteins

Guenther et al., PNAS 105: 17402-17407, Nov 11, 2008

 

Student: Wei-Ching Huang (黃薇靜)

Commentator: Dr. Bei-Chang Yang (楊倍昌 教授)

Time: 15:10-16:00, Apr 07, 2009

Place: Room 602

 

Abstract

Ceramide is the structural precursor of sphingolipids and acts not as inert precursor but has essential roles in many aspects of cell biology, including the regulation of growth arrest, senescence, and apoptosis.1 Alteration of ceramide metabolism has been linked to several diseases such as inflammatory disorders, diabetes, neurodegeneration, and especially cancers. Decreasing cellular ceramide levels increases tumor growth and metastasis and can lead to multidrug resistance.1 Autophagy has also been linked to cancer2 and reported to be induced by ceramide. However, the mechanisms by which ceramide initiates autophagy remain inconclusive. In this study, the authors hypothesized that ceramide stimulates autophagy through inducing starvation by downregulating nutrient transporters. They confirmed that ceramide-induced autophagy precedes cell death and plays protective role upon ceramide insults. Consistent with their hypothesis, either amino acid transporter 4F2 heavy chain (4F2hc) and mCAT-1 or glucose transporter GLUT-1 was downregulated by ceramide. To investigate the dependence of nutrient transporter downregulation in ceramide-induced cell death, by using nystatin (raft disrupting agent to inhibit protein internalization) and MP (methyl pyruvate; membrane permeable nutrient), ceramide-induced cell death was rescued. In addition, autophagy was required for the protective effect of MP. Chemotherapeutic DNR (daunorubicin) treatment increased endogenous ceramide levels and decreased surface expression of 4F2hc followed by cell death. Moreover, sustaining high demand of nutrients sensitized cells to ceramide-induced cell death. In summary, the authors demonstrated that increasing intracellular ceramide levels leads downregulation of nutrient transporter proteins and starves cells to death. In this process, autophagy is triggered by ceramide-induced starvation to protect/delay cell death.

 

References

1. Besim Ogretmen and Yusuf A. Hannun, Biologically active sphingolipids in cancer pathogenesis and treatment. Nat. Rev. Cancer 4: 604-616, 2004

2. Beth Levine1 and Junying Yuan, Autophagy in cell death: an innocent convict? J. Clin. Invest. 115: 2679-2688, 2005