Enhancement of C2-ceramide antitumor activity by small interfering RNA on X chromosome-linked inhibitor of apoptosis protein in resistant human glioma cells.
OBJECTIVE
Many human glioma cells are resistant to ceramide. In this study the authors investigated the mechanisms of that resistance and considered ways to overcome it.


METHODS
The authors first administered C2-ceramide (N-acetylsphingosine) to human glioma cells from rare cell lines susceptible to C2-ceramide (SKMG1 and U87MG) and other cell lines resistant to it (U251SP, T98G, SKAO2, and U251MG). Following this, the authors analyzed the statuses of transduction signals such as cell viability, morphological changes, caspases, mitochondrial membrane potential, apoptosis-inducing factor, oligonucleosomal DNA fragmentation, and the inhibitor of apoptosis protein (IAP) family.


CONCLUSIONS
Ceramide resistance was found to arise from the inhibition of caspase-7 induced by IAPs, especially X chromosome-linked IAP (XIAP). Small interfering RNA (siRNA) on XIAP quenched that resistance in ceramide-resistant human glioma cells (U251SP, T98G, SKAO2, U251MG), indicating that a siRNA for XIAP may be a useful tool for overcoming the resistance to ceramide in human glioma cells.
Hatano
Manabu
M
Department of Neurosurgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Mizuno
Masaaki
M
Yoshida
Jun
J
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D051033:Apoptosis Inducing Factor; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D041321:Chromosomes, Human, X / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004354:Drug Screening Assays, Antitumor; D005420:Flavoproteins / Q000235:genetics; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D011506:Proteins / Q000502:physiology; D034741:RNA, Small Interfering / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051636:X-Linked Inhibitor of Apoptosis Protein
C494829:AIFM1 protein, human; D000970:Antineoplastic Agents; D051033:Apoptosis Inducing Factor; D005420:Flavoproteins; D008565:Membrane Proteins; C064769:N-acetylsphingosine; D011506:Proteins; D034741:RNA, Small Interfering; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D013110:Sphingosine