Department of Genetics, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Neoplasia. 2013 Jul;15(7):738-48. doi: 10.1593/neo.121888.
Alveolar rhabdomyosarcoma (ARMS) has a much poorer prognosis than the more common embryonal subtype. Most ARMS tumors characteristically possess a specific genomic translocation between the genes of PAX3/7 and FOXO1 (FKHR), which forms fusion proteins possessing the DNA binding domains of PAX3/7 and the more transcriptionally potent transactivation domain of FOXO1. We have shown that the proapoptotic BH3-only family member Noxa is upregulated by the PAX3-FOXO1 fusion transcription factor in a p53-independent manner. The increased expression of Noxa renders PAX3-FOXO1-expressing cells more susceptible to apoptosis induced by a γ-secretase inhibitor (GSI1, Z-LLNle-CHO), the proteasome inhibitor bortezomib, and BH3 mimetic ABT-737. Apoptosis in response to bortezomib can be overcome by shRNA knockdown of Noxa. In vivo treatment with bortezomib reduced the growth of tumors derived from a PAX3-FOXO1-expressing primary myoblast tumor model and RH41 xenografts. We therefore demonstrate that PAX3-FOXO1 up-regulation of Noxa represents an unanticipated aspect of ARMS tumor biology that creates a therapeutic window to allow induction of apoptosis in ARMS cells.
肺泡横纹肌肉瘤 (ARMS) 的预后比更常见的胚胎亚型差得多。大多数 ARMS 肿瘤特征性地具有 PAX3/7 和 FOXO1（FKHR）基因之间的特定基因组易位，该易位形成融合蛋白，具有 PAX3/7 的 DNA 结合结构域和 FOXO1 的更转录有效的反式激活结构域。我们已经表明，促凋亡 BH3 仅家族成员 Noxa 被 PAX3-FOXO1 融合转录因子以不依赖 p53 的方式上调。Noxa 的表达增加使表达 PAX3-FOXO1 的细胞对 γ-分泌酶抑制剂 (GSI1，Z-LLNle-CHO)、蛋白酶体抑制剂硼替佐米和 BH3 模拟物 ABT-737 诱导的细胞凋亡更敏感。用 bortezomib 进行细胞凋亡可以通过 shRNA 敲低 Noxa 来克服。用 bortezomib 进行体内治疗可降低源自表达 PAX3-FOXO1 的原代成肌细胞瘤肿瘤模型和 RH41 异种移植物的肿瘤生长。因此，我们证明 PAX3-FOXO1 对 Noxa 的上调代表了 ARMS 肿瘤生物学的一个意外方面，为在 ARMS 细胞中诱导细胞凋亡创造了一个治疗窗口。
