Growth and DNA damage-inducible transcription factor 153 mediates apoptosis in response to fenretinide but not synergy between fenretinide and chemotherapeutic drugs in neuroblastoma
Growth and DNA damage-inducible transcription factor 153 mediates apoptosis in response to fenretinide but not synergy between fenretinide and chemotherapeutic drugs in neuroblastoma
复制标题
DOI：
10.1124/mol.64.6.1370
复制
发表时间：
2003-12-01
影响因子：
3.6
通讯作者：
Redfern, CPF
中科院分区：
文献类型：
--
作者：
Corazzari, M;Lovat, PE;Redfern, CPF
芬维A胺体外诱导神经母细胞瘤细胞凋亡并与化疗药物顺铂和依托泊苷协同作用。被称为生长和DNA损伤（GADD）诱导转录因子153的应激诱导转录因子响应于芬维A胺而被诱导，并且在其他细胞类型中通过BCL 2家族的促凋亡和抗凋亡成员调节凋亡。由于BCL 2家族蛋白在化疗药物诱导的细胞凋亡中起重要作用，因此GADD 153可能是芬维A胺与化疗药物之间协同作用的关键介质。为了研究这一点，GADD 153 cDNA的正义和反义方向稳定转染到SH-SY 5 Y神经母细胞瘤细胞使用四环素诱导载体。GADD 153表达的增加提高了细胞凋亡的背景水平，并增加了芬维A胺或化疗药物顺铂和依托泊苷诱导的细胞凋亡。然而，芬维A胺和化疗药物之间的协同作用没有增加。相反，反义GADD 153的表达几乎取消了响应于芬维A胺的细胞凋亡的诱导，但总体上对化疗药物诱导的细胞凋亡没有显著影响。反义GADD 153对化疗药物和芬维A胺之间的协同作用的影响随所用药物而变化：芬维A胺和顺铂之间的协同作用没有影响，但芬维A胺与依托泊苷的组合成为拮抗性的。这些结果表明，介导芬维A胺和化疗药物之间的协同作用的机制位于GADD 153的上游。
Fenretinide induces apoptosis of neuroblastoma cells in vitro and interacts synergistically with the chemotherapeutic drugs cisplatin and etoposide. The stress-inducible transcription factor known as growth and DNA damage (GADD)-inducible transcription factor 153 is induced in response to fenretinide and in other cell types modulates apoptosis via pro- and antiapoptotic members of the BCL2 family. Because BCL2-family proteins are important in apoptosis induced by chemotherapeutic drugs, GADD153 may be a key mediator of synergy between fenretinide and chemotherapeutic drugs. To investigate this, GADD153 cDNA in sense and antisense orientations was stably transfected into SH-SY5Y neuroblastoma cells using a tetracycline-inducible vector. Increased expression of GADD153 raised the background level of apoptosis and increased apoptosis induced by fenretinide or the chemotherapeutic drugs cisplatin and etoposide. However, there was no increase in synergy between fenretinide and chemotherapeutic drugs. Conversely, expression of antisense-GADD153 virtually abolished the induction of apoptosis in response to fenretinide but overall had no significant effect on apoptosis induced by chemotherapeutic drugs. The effect of antisense-GADD153 on synergy between chemotherapeutic drugs and fenretinide varied with the drug used: there was no effect on synergy between fenretinide and cisplatin, but the combination of fenretinide with etoposide became antagonistic. These results suggest that mechanisms mediating synergy between fenretinide and chemotherapeutic drugs lie upstream of GADD153.