Ceramide induces p38 MAPK and JNK activation through a mechanism involving a thioredoxin-interacting protein-mediated pathway

Chia-Ling Chen, Chiou Feng Lin, Wen-Tsan Chang, Wei-Ching Huang, Chiao-Fang Teng, Yee-Shin Lin

Research output: Contribution to journalArticle

126 Citations (Scopus)

Abstract

Ceramide, a tumor-suppressor lipid, is generated by sphingomyelin hydrolysis or by de novo synthesis when cells are activated by various stress stimuli as well as when cancer cells are subjected to genotoxic chemotherapy. Ceramide may modulate apoptotic signaling pathways; however, its transcription-dependent effects remain unclear. Our data showed that actinomycin D partially inhibited ceramide-induced apoptosis. Using mi-croarray analysis, we found that ceramide up-regulated a tumor suppressor gene called thioredoxin-interacting protein (Txnip). Similarly, the chemotherapeu-tic agent etoposide induced Txnip expression en route to apoptosis, which was blocked by inhibitors of ceramide production. Txnip colocalized with thioredoxin and reduced its activity, which caused dissociation of thioredoxin from apoptosis signal-regulating kinase 1 (ASK1). Cells expressing ASK1 siRNA were more resistant to ceramide-induced apoptosis. Ceramide caused ASK1-regulated p38 mitogen-activated protein kinase (MAPK) and JNK activation, as well as activation of the endoplasmic reticulum (ER) stress cascade, and pharmacologic or siRNA-mediated inhibition of p38 MAPK or JNK partially reduced ceramide-induced mitochondria-mediated apoptosis. Furthermore, ceramide-induced ASK1, p38. and JNK phosphorylation and cell apoptosis were inhibited by Txnip siRNA trans- fection. Taken together, we show that ceramide exhibits a mechanism of transcriptional regulation involving up- regulation of Txnip expression, also induced by etoposide, which results in ASK1 activation, ER stress, and p38 and JNK phosphorylation, all leading to apo-ptosis.

Original languageEnglish
Pages (from-to)4365-4374
Number of pages10
JournalBlood
Volume111
Issue number8
DOIs
Publication statusPublished - Apr 15 2008

Fingerprint

Thioredoxins
Ceramides
p38 Mitogen-Activated Protein Kinases
MAP Kinase Kinase Kinase 5
Chemical activation
Proteins
Apoptosis
Small Interfering RNA
Phosphorylation
Endoplasmic Reticulum Stress
Etoposide
Tumors
Cells
Tics
Mitochondria
Chemotherapy
Sphingomyelins
Dactinomycin
Cell death
Transcription

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Ceramide induces p38 MAPK and JNK activation through a mechanism involving a thioredoxin-interacting protein-mediated pathway. / Chen, Chia-Ling; Lin, Chiou Feng; Chang, Wen-Tsan; Huang, Wei-Ching; Teng, Chiao-Fang; Lin, Yee-Shin.

In: Blood, Vol. 111, No. 8, 15.04.2008, p. 4365-4374.

Research output: Contribution to journalArticle

Chen, Chia-Ling ; Lin, Chiou Feng ; Chang, Wen-Tsan ; Huang, Wei-Ching ; Teng, Chiao-Fang ; Lin, Yee-Shin. / Ceramide induces p38 MAPK and JNK activation through a mechanism involving a thioredoxin-interacting protein-mediated pathway. In: Blood. 2008 ; Vol. 111, No. 8. pp. 4365-4374.
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