Involvement of glyceraldehyde-3-phosphate dehydrogenase in tumor necrosis factor-related apoptosis-inducing ligand-mediated death of thyroid cancer cells.
TNF-related apoptosis-inducing ligand (TRAIL) is cytotoxic to most thyroid cancer cell lines, including those originating from anaplastic carcinomas, implying TRAIL as a promising therapeutic agent against thyroid cancers. However, signal transduction in TRAIL-mediated apoptosis is not clearly understood. In addition to its well-known glycolytic functions, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a multifunctional protein, including its surprising role as a mediator for cell death. In this study we explored the involvement of GAPDH in TRAIL-mediated thyroid cancer cell death. In follicular undifferentiated thyroid cells, S-nitrosylation and nuclear translocation of GAPDH appear to mediate TRAIL-induced cell death at least partially, as evidenced by pretreatment with N-nitro-L-arginine methyl ester, a competitive nitric oxide synthase inhibitor that partially but significantly attenuated TRAIL-induced apoptosis through the reduction of S-nitrosylation and nuclear translocation of GAPDH. In addition, GAPDH small interfering RNA partially prevented the apoptotic effect of TRAIL, although TRAIL-induced nitric oxide synthase stimulation and production of nitric oxide were not attenuated. Furthermore, nuclear localization of GAPDH was observed in another thyroid cancer cell line, KTC2, which is also sensitive to TRAIL, but not in those TRAIL insensitive cell lines: ARO, KTC1, and KTC3. These data indicate that nitric oxide-mediated S-nitrosylation of GAPDH and subsequent nuclear translocation of GAPDH might function as a mediator of TRAIL-induced cell death in thyroid cancer cells.
Du
Zhen-Xian
ZX
Department of Endocrinology and Metabolism, the 1st Affiliated Hospital, China Medical University, Shenyang 110001, China. dzx_doctor@hotmail.com
Wang
Hua-Qin
HQ
Zhang
Hai-Yan
HY
Gao
Da-Xin
DX
D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+) / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*; D013964:Thyroid Neoplasms / Q000473:pathology*
D012334:RNA, Neoplasm; D053221:TNF-Related Apoptosis-Inducing Ligand; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+); D053148:Caspase 3