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- Title
p53-Independent ceramide formation in human glioma cells during ?-radiation-induced apoptosis.
- Authors
Hara, S.; Nakashima, S.; Kiyono, T.; Sawada, M.; Yoshimura, S.; Iwama, T.; Banno, Y.; Shinoda, J.; Sakai, N.
- Abstract
Although the p53 tumor-suppressor gene product plays a critical role in apoptotic cell death induced by DNA-damaging chemotherapeutic agents, human glioma cells with functional p53 were more resistant to ?-radiation than those with mutant p53. U-87 MG cells with wild-type p53 were resistant to ?-radiation. U87-W E6 cells that lost functional p53, by the expression of type 16 human papillomavirus E6 oncoprotein, became susceptible to radiation-induced apoptosis. The formation of ceramide by acid sphingomyelinase (A-SMase), but not by neutral sphingomyelinase, was associated with p53-independent apoptosis. SR33557 (2-isopropyl-1-(4-[3-N-methyl-N-(3,4-dimethoxybphenethyl)amino]propyloxy)benzene-sulfonyl) indolizine, an inhibitor of A-SMase, suppressed radiation-induced apoptotic cell death. In contrast, radiation-induced A-SMase activation was blocked in glioma cells with endogenous functional p53. The expression of acid ceramidase was induced by ?-radiation, and was more evident in cells with functional p53. N-oleoylethanolamine, which is known to inhibit ceramidase activity, unexpectedly downregulated acid ceramidase and accelerated radiation-induced apoptosis in U87-W E6 cells. Moreover, cells with functional p53 could be sensitized to ?-radiation by N-oleoylethanolamine, which suppressed radiation-induced acid ceramidase expression and then enhanced ceramide formation. Sensitization to ?-radiation was also observed in U87-MG cells depleted of functional p53 by retroviral expression of small interfering RNA. These results indicate that ceramide may function as a mediator of p53-independent apoptosis in human glioma cells in response to ?-radiation, and suggest that p53-dependent expression of acid ceramidase and blockage of A-SMase activation play pivotal roles in protection from ?-radiation of cells with endogenous functional p53.Cell Death and Differentiation (2004) 11, 853-861. doi:10.1038/sj.cdd.4401428 Published online 16 April 2004
- Subjects
GLIOMAS; NERVOUS system tumors; CYTOLOGICAL research; MOLECULAR biology; BIOCHEMISTRY; APOPTOSIS; CELL death
- Publication
Cell Death & Differentiation, 2004, Vol 11, Issue 8, p853
- ISSN
1350-9047
- Publication type
Article
- DOI
10.1038/sj.cdd.4401428