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Indomethacin induced glioma apoptosis involving ceramide signals

Journal Article · · Experimental Cell Research
 [1];  [2];  [3];  [4];  [5];  [6];  [7];  [5]
  1. Department of Surgery, Feng Yuan Hospital, Taichung City 420 (China)
  2. Division of Urology, Taichung Veterans General Hospital, Taichung City 407 (China)
  3. Department of Anesthesiology, Taichung Veterans General Hospital, Taichung City 407 (China)
  4. Department of Pediatrics & Child Health Care, Taichung Veterans General Hospital, Taichung City 407 (China)
  5. Department of Medical Research, Taichung Veterans General Hospital, No. 1650, Section 4, Taiwan Boulevard, Taichung City 407 (China)
  6. Department of Veterinary Medicine, National Chung Hsing University, Taichung City 402 (China)
  7. Department of Nursing, HungKuang University, Taichung City 433 (China)
+ Show Author Affiliations
Highlights: • Indomethacin induced glioma cell apoptosis. • Indomethacin increased intracellular ceramide levels. • Ceramide induced glioma cell apoptosis. • LY294002 induced glioma cell apoptosis. • Ceramide/PP2A/Akt/Mcl-1, FLIP axis involved in indomethacin-induced apoptosis. Nonsteroidal anti-inflammatory drugs (NSAIDs) are increasingly implicated in the prevention and treatment of cancers apart from their known inhibitory effects on eicosanoid production. One of the NSAIDs, indomethacin, in particular shows promising antineoplastic outcome against glioma. To extend such finding, we here studied in human H4 and U87 glioma cells the possible involvement of the ceramide/protein phosphatase 2 A (PP2A)/Akt axis in the indomethacin-induced apoptosis. We found that the induced apoptosis was accompanied by a series of biochemical events, including intracellular ceramide generation, PP2A activation, Akt dephosphorylation, Mcl-1 and FLICE inhibiting protein (FLIP) transcriptional downregulation, Bax mitochondrial distribution, and caspase 3 activation. Such events were also duplicated with a cell-permeable C2-ceramide and Akt inhibitor LY294002. Pharmacological inhibition of ceramide synthase by fumonisin B1 and PP2A by okadaic acid moderately attenuated indomethacin-induced Akt dephosphorylation along with the apoptosis. Results suggested that the ceramide/PP2A/Akt axis is involved in the apoptosis and a possible cyclooxygenase-independent target for indomethacin. Furthermore, apoptosis regulatory proteins such as Mcl-1 and FLIP are potential downstream effectors of this axis and their downregulation could turn on the apoptotic program.
OSTI ID:
23082420
Journal Information:
Experimental Cell Research, Journal Name: Experimental Cell Research Journal Issue: 1 Vol. 365; ISSN 0014-4827; ISSN ECREAL
Country of Publication:
United States
Language:
English

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Related Subjects

60 APPLIED LIFE SCIENCES
APOPTOSIS
DRUGS
GLIOMAS
INFLAMMATION
MITOCHONDRIA
PHOSPHATASES