Repositioning Bazedoxifene as a novel IL-6/GP130 signaling antagonist for human rhabdomyosarcoma therapy.
Repositioning Bazedoxifene as a novel IL-6/GP130 signaling antagonist for human rhabdomyosarcoma therapy.
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DOI：
10.1371/journal.pone.0180297
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Lin J
中科院分区：
文献类型：
--
作者：
Xiao H;Bid HK;Chen X;Wu X;Wei J;Bian Y;Zhao C;Li H;Li C;Lin J
由于白细胞介素-6 (IL-6)/GP130信号通路在多种类型癌症的生存和进展中起着关键作用，因此它是癌症治疗的一个有希望的靶点。我们已经确定了Bazedoxifene，一种美国食品和药物管理局（FDA）批准用于预防绝经后骨质疏松症的药物，具有IL-6/GP130相互作用抑制剂的新功能。在本研究中，我们研究了巴泽多昔芬在横纹肌肉瘤中的作用，并评估抑制IL-6/GP130信号传导是否为横纹肌肉瘤的有效治疗策略。体外观察巴塞多西芬对横纹肌肉瘤细胞株的抑制作用，并采用RH30异种移植模型进一步观察巴塞多西芬对肿瘤生长的抑制作用。横纹肌肉瘤细胞对基因敲低或中和抗体抑制GP130表现出敏感性，提示IL-6/GP130是横纹肌肉瘤细胞的治疗靶点。巴泽多昔芬降低转录3 （STAT3）信号转导和激活因子磷酸化，阻断STAT3的DNA结合，下调STAT3下游基因的表达。巴泽多昔芬还能诱导横纹肌肉瘤细胞凋亡，降低细胞活力，抑制细胞集落形成。通过添加过量的IL-6或组成型STAT3的过表达，巴泽多西芬处理后对集落形成、STAT3磷酸化或细胞活力的抑制分别部分逆转，支持巴泽多西芬通过IL-6/GP130信号传导起作用。此外，贝塞多昔芬还能抑制体外细胞侵袭和血管生成。此外，口服巴泽多昔芬可显著抑制移植人横纹肌肉瘤裸鼠的肿瘤生长和STAT3磷酸化表达。综上所述，这些发现验证了IL-6/GP130信号作为横纹肌肉瘤的治疗靶点，并首次证明了巴泽多昔芬可能作为一种靶向IL-6/GP130治疗横纹肌肉瘤的新药。
Interleukins-6 (IL-6)/GP130 signaling pathway represents a promising target for cancer therapy due to its critical role in survival and progression of multiple types of cancer. We have identified Bazedoxifene, a Food and Drug Administration (FDA)-approved drug used for the prevention of postmenopausal osteoporosis, with novel function as inhibitor of IL-6/GP130 interaction. In this study, we investigate the effect of Bazedoxifene in rhabdomyosarcoma and evaluate whether inhibiting IL-6/GP130 signaling is an effective therapeutic strategy for rhabdomyosarcoma. The inhibitory effect of Bazedoxifene was assessed in rhabdomyosarcoma cell lines in vitro and RH30 xenograft model was used to further examine the suppressive efficacy of Bazedoxifene on tumor growth in vivo. Rhabdomyosarcoma cells showed their sensitivity to GP130 inhibition using gene knockdown or neutralized antibody, suggesting IL-6/GP130 as therapeutic target in rhabdomyosarcoma cells. Bazedoxifene decreased the signal transducer and activator of transcription3 (STAT3) phosphorylation, blocked STAT3 DNA binding, and down-regulated the expression of STAT3 downstream genes. Bazedoxifene also induced cell apoptosis, reduced cell viability, and inhibited colony formation in rhabdomyosarcoma cells. The inhibition of colony formation, STAT3 phosphorylation, or cell viability following Bazedoxifene treatment was partially reversed by addition of excess IL-6 or overexpression of constitutive STAT3, respectively, supporting Bazedoxifene acted through IL-6/GP130 signaling. In addition, Bazedoxifene repressed cell invasion and angiogenesis in vitro. Furthermore, oral administration of Bazedoxifene significantly suppressed tumor growth and expression of STAT3 phosphorylation in nude mice bearing established human rhabdomyosarcoma xenograft. Taken together, these findings validate IL-6/GP130 signaling as therapeutic target in rhabdomyosarcoma and provide first evidence that Bazedoxifene may serve as a novel promising drug targeting IL-6/GP130 for treatment of rhabdomyosarcoma.