Ceramide-induced apoptosis of human thyroid cancer cells resistant to apoptosis by irradiation.
Ionizing radiation (IR) induces apoptosis through, in part, cell membrane breakdown signals. Ceramide and diacylglycerol (DAG) are released after IR exposure, which act as second messengers to induce proapoptotic and antiapoptotic signals, respectively. We have previously shown, however, that thyroid cells are relatively resistant to IR-induced apoptosis. To investigate the mechanism of thyroid cell resistance to IR-related apoptosis, we determined the effects of ceramide and its release following exposure of human thyroid cancer cell lines to IR. Exogenous C2-ceramide (10-100 microM) activated the apoptosis process in all cell lines used. Exogenous C2-ceramide also activated a stress kinase, c-Jun N-terminal kinase UNK). The apoptotic action of ceramide was attenuated by serum or simultaneous activation of protein kinases C and A by phorbol esters and forskolin. Furthermore, 2-5 Gy IR had a differential effect on ceramide and DAG release in human thyroid cells; a weak and transient release of ceramide but a strong and sustained release of DAG. Our results indicated that the radioresistance properties of thyroid cancer cells probably reflect the dominance of anti-apoptotic signals, evoked by growth factor(s) and DAG, which override the apoptotic effect of ceramide released by human thyroid cells on exposure to IR, in spite of activation of proapoptotic pathway downstream of ceramide.
Sautin
Y
Y
Department of International Health and Radiation Research, Atomic Bomb Disease Institute, Nagasaki University School of Medicine, Japan.
Takamura
N
N
Shklyaev
S
S
Nagayama
Y
Y
Ohtsuru
A
A
Namba
H
H
Yamashita
S
S
D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D001769:Blood; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004075:Diglycerides / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005720:Gamma Rays; D006801:Humans; D020287:In Situ Nick-End Labeling; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D015290:Second Messenger Systems; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D013964:Thyroid Neoplasms / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured
D004075:Diglycerides; C064769:N-acetylsphingosine; D010703:Phorbol Esters; D005576:Colforsin; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D013110:Sphingosine