p53-Independent ceramide formation in human glioma cells during γ-radiation-induced apoptosis

Abstract

AbstractAlthough 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 γ-radiation than those with mutant p53. U-87 MG cells with wild-type p53 were resistant to γ-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 γ-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 γ-radiation by N-oleoylethanolamine, which suppressed radiation-induced acid ceramidase expression and then enhanced ceramide formation. Sensitization to γ-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 γ-radiation, and suggest that p53-dependent expression of acid ceramidase and blockage of A-SMase activation play pivotal roles in protection from γ-radiation of cells with endogenous functional p53.

DOI: 10.1038/sj.cdd.4401428

Cite this paper

@article{Hara2004p53IndependentCF, title={p53-Independent ceramide formation in human glioma cells during γ-radiation-induced apoptosis}, author={S Hara and Shigeru Nakashima and Tohru Kiyono and Masashi Sawada and Shinichi Yoshimura and Toru Iwama and Y. Banno and Jun Shinoda and Nobuyuki Sakai}, journal={Cell Death and Differentiation}, year={2004}, volume={11}, pages={853-861} }