Center for Childhood Cancer, The Research Institute at Nationwide Children's Hospital, The Ohio State University, College of Medicine, Columbus, OH 43205, USA.
Biochem Biophys Res Commun. 2011 Apr 15;407(3):450-5. doi: 10.1016/j.bbrc.2011.03.014. Epub 2011 Mar 21.
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in the pediatric and adolescent population. Though treatments for localized disease have reasonable long-term success rates, if disease is diffuse at diagnosis, outcomes are far poorer. Additional and/or alternative therapies are critical for improved clinical outcomes. One potentially therapeutic target is the signal transducer and activator of transcription 3 (STAT3) pathway. STAT3 has been shown to have constitutive activation in human rhabdomyosarcoma cells; thus, inhibition of STAT3 signaling may be a mechanism to induce tumor cell death. Celecoxib has been shown, by computer modeling, to bind STAT3 at the SH2 domain and competitively inhibit native peptide binding necessary for phosphorylation and subsequent propagation of the STAT3 signaling cascade. We found that celecoxib inhibits IL-6-induced and persistent STAT3 phosphorylation and inhibits cell viability in human rhabdomyosarcoma cells. We found that genes downstream of STAT3 (BCL-2, survivin, cyclin D1) were downregulated with celecoxib. Celecoxib also inhibits colony formation and cell migration. Our results suggest that, though known more commonly as a cyclooxygenase-2 (COX-2) inhibitor, celecoxib could act through the STAT3 pathway as well. More importantly, its effect on cell migration and clonogenic colony forming ability make it a potentially useful therapeutic agent for rhabdomyosarcoma, especially in metastatic disease whose clinical outcome is marginal at best with current therapies.
横纹肌肉瘤（RMS）是儿童和青少年人群中最常见的软组织肉瘤。虽然局部疾病的治疗有合理的长期成功率，但如果疾病在诊断时已经扩散，预后则差得多。额外的和/或替代疗法对于改善临床结果至关重要。一个潜在的治疗靶点是信号转导和转录激活因子 3（STAT3）通路。已经表明，人类横纹肌肉瘤细胞中的 STAT3 持续激活；因此，抑制 STAT3 信号可能是诱导肿瘤细胞死亡的一种机制。计算机建模表明，塞来昔布可以在 SH2 结构域与 STAT3 结合，并竞争性抑制天然肽结合，从而抑制磷酸化和随后的 STAT3 信号级联的传播。我们发现塞来昔布可抑制 IL-6 诱导的和持续的 STAT3 磷酸化，并抑制人横纹肌肉瘤细胞的细胞活力。我们发现 STAT3 下游的基因（BCL-2、存活素、细胞周期蛋白 D1）下调与塞来昔布有关。塞来昔布还抑制集落形成和细胞迁移。我们的结果表明，尽管塞来昔布更常被认为是一种环氧化酶-2（COX-2）抑制剂，但它也可以通过 STAT3 途径发挥作用。更重要的是，它对细胞迁移和克隆形成能力的影响使其成为横纹肌肉瘤的一种潜在有用的治疗剂，尤其是在转移性疾病中，目前的治疗方法对其预后影响甚微。
